NOVEL PYRIMIDINE COMPOUNDS AS mTOR AND PI3K INHIBITORS

ABSTRACT

The present invention relates to pyrimidine compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     which are useful in treating mTOR kinase- or PI3K kinase-related diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 14/192,301filed Feb. 27, 2014, which is a continuation-in-part of U.S. applicationSer. No. 13/519,535 filed Jun. 27, 2012, which is a 371 ofPCT/M2010/003347 filed Dec. 27, 2010, which claims priority to U.S.Provisional Application No. 61/290,437 filed Dec. 28, 2009, the contentsof all of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel pyrimidine compounds and theiruse in treating PI3K kinase- and/or mTOR kinase-related diseases.

BACKGROUND OF THE INVENTION

The mammalian target of Rapamycin, mTOR, is a cell-signaling proteinthat regulates the response of tumor cells to nutrients and growthfactors, as well as controlling tumor blood supply through effects onVascular Endothelial Growth Factor, VEGF. Inhibitors of mTOR starvecancer cells and shrink tumors by inhibiting the effect of mTOR. Thereare two important effects as mTOR inhibitors bind to the mTOR kinase.First, mTOR is a downstream mediator of the PI3K/Akt pathway. ThePI3K/Akt pathway is thought to be over-activated in numerous cancers andmay account for the widespread response from various cancers to mTORinhibitors. The over-activation of the upstream pathway would normallycause mTOR kinase to be over-activated as well. However, in the presenceof mTOR inhibitors, this process is blocked. The blocking effectprevents mTOR from signaling to downstream pathways that control cellgrowth. Over-activation of the PI3K/Akt kinase pathway is frequentlyassociated with mutations in the PTEN gene, which is common in manycancers and may help predict what tumors will respond to mTORinhibitors. The second major effect of mTOR inhibition isantiangiogenesis via the lowering of VEGF levels. These anticancer drugshave shown exceptional promise in cancer therapy and may change the waymany types of cancer are treated.

Several studies have demonstrated that mTOR has a central role incontrolling cell growth, proliferation and metabolism. mTOR regulates awide range of cellular functions, including translation, transcription,mRNA turnover, protein stability, actin cytoskeletal organization andautophagy. mTOR is a member of the phosphoinositide kinase-relatedkinase (PIKK) family, but is not a phosphorylating phosphoinositide, aphosphorylate protein on serine or a threonine residue. There are twomTOR complexes in mammalian cells. mTOR complex I (mTORC1) is araptor-mTOR complex, which mainly regulates cell growth in arapamycin-sensitive manner, whereas mTOR complex II (mTORC2) is arictor-mTOR complex, which regulates cytoskeletal organization in arapamycin-insensitive manner.

Kinase subunits of both mTORC1 and mTORC2 regulate cell growth andsurvival in response to nutrient and hormonal signals. mTORC1 isactivated in response to growth factors or amino-acids.Amino-acid-signaling to mTORC1 is mediated by Rag GTPases, which causeamino-acid-induced relocalization of mTOR within the endomembranesystem. Growth-factor-stimulated mTORC1 activation involvesAKT1-mediated phosphorylation of TSC1-TSC2, which leads to theactivation of the Rheb GTPase that potently activates the protein kinaseactivity of mTORC1. Activated mTORC1 up-regulates protein synthesis byphosphorylating key regulators of mRNA translation and ribosomesynthesis. mTORC1 phosphorylates eIF4EBP1 and releases it frominhibiting the elongation initiation factor 4E (eIF4E). mTORC1phosphorylates and activates S6K1 at Thr-421, which then promotesprotein synthesis by phosphorylating PDCD4 and targeting it fordegradation. mTORC2 is also activated by growth factors, but seems to benutrient-insensitive. mTORC2 seems to function upstream of Rho GTPasesto regulate the actin cytoskeleton, probably by activating one or moreRho-type guanine nucleotide exchange factors. mTORC2 promotes theserum-induced formation of stress-fibers or F-actin. mTORC2 plays acritical role in AKT1 Ser-473 phosphorylation, which may facilitate thephosphorylation of the activation loop of AKT1 on Thr-308 by PDK1, whichis a prerequisite for full activation. mTORC2 regulates thephosphorylation of SGK1 at Ser-422. mTORC2 also modulates thephosphorylation of PRKCA on Ser-657.

With the recent discovery of rapamycin independent function of mTOR (bymTOR2) in phosphorylation AKT (at S473), which is important inregulation of cell survival and modulation of PKCα, which plays a majorrole in regulation of actin cytoskeletal organization, it is believedthat inhibition of mTOR function by rapamycin is partial. Therefore, asmall molecule designed to compete with ATP in the catalytic site ofmTOR would be expected to inhibit all of the kinase-dependent functionsof mTORC1 and mTORC2, unlike rapalogs that only target mTORC1. Here wedescribe the discovery of direct mTOR kinase inhibitors which can beused in the treatment of a variety of cancers, including breast, lung,kidney, prostate, blood, liver, and ovarian cancers, and lymphoma andother indications such as rheumatoid arthritis, hamartoma syndromes,transplant rejection, multiple sclerosis and immunosuppression.

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of thephospholipids in cell membranes. In recent years it has become clearthat PI also plays an important role in intracellular signaltransduction. In particular, it is well recognized in the art that PI(4,5) bisphosphate (PI(4,5)P2) is degraded into diacylglycerol andinositol (1,4,5) triphosphate by phospholipase C to induce activation ofprotein kinase C and intracellular calcium mobilization, respectively[M. J. Berridge et al., Nature, 312, 315 (1984); Y. Nishizuka, Science,225, 1365 (1984)].

PI3K was originally considered to be a single enzyme, but it has nowbeen clarified that a plurality of subtypes is present in PI3K. Eachsubtype has its own mechanism for regulating activity. The PI3K familycomprises at least 15 different enzymes sub-classified by structuralhomology and divided into 3 classes based on sequence homology and theproduct formed by enzyme catalysis. The class I PI3 kinases are composedof 2 subunits: a 110 kd catalytic subunit and an 85 kd regulatorysubunit. The regulatory subunits contain SH2 domains and bind totyrosine residues phosphorylated by growth factor receptors with atyrosine kinase activity or oncogene products, thereby inducing the PI3Kactivity of the p110α catalytic subunit which phosphorylates its lipidsubstrate. Class I PI3Ks are further divided into two groups, class Iaand class Ib, in terms of their activation mechanism. Class Ia PI3Ksinclude PI3K p110α, p110β and p110δ subtypes, which transmit signalsfrom tyrosine kinase-coupled receptors. Class Ib PI3K includes a p110γsubtype activated by a G protein-coupled receptor. PI and PI(4)P areknown as substrates for class II PI3Ks. Class II PI3Ks include PI3K C2α,C2β and C2γ subtypes, which are characterized by containing C2 domainsat the C terminus. The substrate for class III PI3Ks is PI only.

Most if not all of the non-rapalog mTOR inhibitors described to date inthe scientific literature were developed to inhibit other enzymes,especially class I PI3Ks. Because PI3K regulates mTOR activity,inhibitors that target both enzymes are generally not useful as researchtools to study mTOR regulation or function. However, drugs that are dualPI3K/mTOR inhibitors might have a therapeutic advantage oversingle-target inhibitors in certain disease settings. PI3K inhibitorsand mTOR inhibitors are expected to be novel types of medicaments usefulagainst cell proliferation disorders, especially as carcinostaticagents. Thus, it would be advantageous to have new mTOR inhibitors andPI3K inhibitors as potential treatment regimens for mTOR kinase- andPI3K kinase-related diseases.

SUMMARY OF THE INVENTION

It has now been found that a series of novel pyrimidine compounds haveactivity as inhibitors of mTOR and PI3K. Accordingly, the presentinvention provides a compound of formula (I):

wherein

R¹ is selected from:

(i) a group of the following formula:

wherein

P is aryl or heteroaryl which is unsubstituted or substituted, whereinwhen P is a benzoimidazole group, said benzoimidazole group is attachedto the pyrimidinyl group in formula (I) through its benzene ring;

Q is selected from —H, —OR, —SR, -Halo, —NR₃R₄, —OS(O)_(m)R, —OC(O)R,—OC(O)NHR, —S(O)_(m)NR₃R₄, —NRC(O)R, —NRS(O)_(m)R, —NRC(O)NR₃R₄, and—NRC(S)NR₃R₄, wherein each R, R₃, and R₄ is independently selected fromH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and a 5- to 12-membered carbocyclicgroup, aryl or heteroaryl group, the group being unsubstituted orsubstituted; m is 1 or 2; or R₃ and R₄, which are the same or different,are each independently selected from H, C₁-C₆ alkyl which isunsubstituted or substituted, C₃-C₁₀ cycloalkyl which is unsubstitutedor substituted, —C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are asdefined above, or R₃ and R₄ together with the nitrogen atom to whichthey are attached form a saturated 5-, 6- or 7-membered N-containingheterocyclic group which is unsubstituted or substituted; —C(O)R,—C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above;

Y is selected from —O—(CH₂)_(n)—, —S—(CH₂)_(n)—, and —S(O)_(m)(CH₂)_(n)—wherein m is 1 or 2, n is 0 or an integer of 1 to 3, and R² is selectedfrom H or a 5- to 12-membered carbocyclic or heterocyclic group which isunsubstituted or substituted, and a group —NR₃R₄ wherein R₃ and R₄ areas defined above;

Z is selected from (i) halo, —(CH₂)_(s)—COOR, —(CH₂)_(s)CHO,—(CH₂)CH₂OR, —(CH₂)_(s)CONR₃R₄, —(CH₂)_(s)CH₂NR₃R₄, —NR₃R₄ and—O(CH₂)_(s)NR₃R₄ wherein s is 0 or an integer of 1 to 2 and wherein R,R₃ and R₄ are as defined above; (ii) substituted or unsubstitutedheteroaryl, (iii) substituted or unsubstituted heterocyclyl, (iv)substituted or unsubstituted aryl, and (v) substituted or unsubstitutedC₁-C₆-alkyl; and W is selected from (i) NR₅R₆, wherein R₅ and R₆ form,together with the N atom to which they are attached, a morpholine ringwhich is unsubstituted or substituted, (ii) substituted or unsubstitutedheteroaryl, (iii) substituted or unsubstituted heterocyclyl, (iv)substituted or unsubstituted aryl, and (v) substituted or unsubstitutedC₁-C₆-alkyl; or a stereoisomer, or a tautomer, or an N-oxide, or apharmaceutically acceptable salt, or an ester, or a prodrug, or ahydrate, or a solvate thereof.

Provided herein are pharmaceutical compositions comprising the compoundof formula (I), or a stereoisomer, or a tautomer, or an N-oxide, or apharmaceutically acceptable salt, or an ester, or a prodrug, or ahydrate, or a solvate thereof, and a pharmaceutically acceptable carrieror diluent.

Further provided herein is a method for treating mTOR kinase-/PI3Kkinase-related diseases, which comprises administering to a subject aneffective amount of the compound of formula (I), or a stereoisomer, or atautomer, or an N-oxide, or a pharmaceutically acceptable salt, or anester, or a prodrug, or a hydrate, or a solvate thereof.

Additionally provided herein is a method for preparing the compound offormula (I), or a stereoisomer, or a tautomer, or an N-oxide, or apharmaceutically acceptable salt, or an ester, or a prodrug, or ahydrate, or a solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I):

wherein

R¹ is selected from:

(i) a group of the following formula:

wherein P is aryl or heteroaryl which is unsubstituted or substituted,wherein when P is a benzoimidazole group, said benzoimidazole group isattached to the pyrimidinyl group in formula (I) through its benzenering;

Q is selected from —H, —OR, —SR, -Halo, —NR₃R₄, —OS(O)_(m)R, —OC(O)R,—OC(O)NHR, —S(O)_(m)NR₃R₄, —NRC(O)R, —NRS(O)_(m)R, —NRC(O)NR₃R₄, and—NRC(S)NR₃R₄, wherein each R, R₃, and R₄ is independently selected fromH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and a 5- to 12-membered carbocyclicgroup, aryl or heteroaryl group, the group being unsubstituted orsubstituted; m is 1 or 2; or R₃ and R₄, which are the same or different,are each independently selected from H, C₁-C₆ alkyl which isunsubstituted or substituted, C₃-C₁₀ cycloalkyl which is unsubstitutedor substituted, —C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are asdefined above, or R₃ and R₄ together with the nitrogen atom to whichthey are attached form a saturated 5-, 6- or 7-membered N-containingheterocyclic group which is unsubstituted or substituted; —C(O)R,—C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above;

Y is selected from —O—(CH₂)_(n)—, —S—(CH₂)_(n)—, and —S(O)_(m)(CH₂)_(n)—wherein m is 1 or 2, n is 0 or an integer of 1 to 3, and R² is selectedfrom H or a 5- to 12-membered carbocyclic or heterocyclic group which isunsubstituted or substituted, and a group —NR₃R₄ wherein R₃ and R₄ areas defined above;

Z is selected from (i) halo, —(CH₂)_(s)—COOR, —(CH₂)_(s)CHO,—(CH₂)_(s)CH₂OR, —(CH₂)_(s)CONR₃R₄, —(CH₂)_(s)CH₂NR₃R₄, —NR₃R₄ and—O(CH₂)_(s)NR₃R₄ wherein s is 0 or an integer of 1 to 2 and wherein R,R₃ and R₄ are as defined above; (ii) substituted or unsubstitutedheteroaryl, (iii) substituted or unsubstituted heterocyclyl, (iv)substituted or unsubstituted aryl, and (v) substituted or unsubstitutedC₁-C₆-alkyl; and

W is selected from (i) NR₅R₆, wherein R₅ and R₆ form, together with theN atom to which they are attached, a morpholine ring which isunsubstituted or substituted, (ii) substituted or unsubstitutedheteroaryl, (iii) substituted or unsubstituted heterocyclyl, (iv)substituted or unsubstituted aryl, and (v) substituted or unsubstitutedC₁-C₆-alkyl; or a stereoisomer, or a tautomer, or an N-oxide, or apharmaceutically acceptable salt, or an ester, or a prodrug, or ahydrate, or a solvate thereof.

Preferably, P is a heteroaryl group selected from:

-   (a) an indazole group which is unsubstituted or substituted;-   (b) an indole group which is unsubstituted or substituted; and-   (c) a benzoimidazole group of the formula

which is unsubstituted or substituted.

A C₁-C₆ alkyl group is linear or branched. Preferably, the alkyl is aC₁-C₄ alkyl group. A C₁-C₆ alkyl group can be unsubstituted orsubstituted with one or more groups Z as defined above. Examples of aC₁-C₆ alkyl group include, but are not limited to, methyl, ethyl, propyl(including all isomeric forms), n-propyl, isopropyl, butyl (includingall isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl(including all isomeric forms), and hexyl (including all isomericforms).

A halogen is F, Cl, Br or I. Preferably, it is F, Cl or Br. A C₁-C₆alkyl group substituted by halogen may be denoted by the term“halo-C₁-C₆ alkyl,” which means an alkyl group in which one or morehydrogen atoms are replaced by halo. A halo-C₁-C₆ alkyl group preferablycontains one, two or three halo groups. A preferred halo-C₁-C₆ alkylgroup is trifluoromethyl.

A C₃-C₁₀ cycloalkyl group may be saturated or unsaturated but anon-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclicgroup having 3 to 10 carbon atoms. The cycloalkyl group preferably has 3to 8, more preferably has 3 to 6 carbon atoms. Examples of a C₃-C₁₀cycloalkyl group include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl, and cycloheptenyl. A C₃-C₁₀ cycloalkylgroup can be unsubstituted or substituted with one or more groups Z asdefined above.

An unsaturated 5- to 12-membered carbocyclic group is a 5-, 6-, 7-, 8-,9-, 10-, 11- or 12-membered carbocyclic ring containing at least oneunsaturated bond. It is a monocyclic or fused bicyclic ring system. Thegroup is aromatic or non-aromatic, for instance a 5- to 12-membered arylgroup. Examples of an unsaturated 5- to 12-membered carbocyclic groupinclude, but are not limited to, phenyl, naphthyl, indanyl, indenyl andtetrahydronaphthyl groups. The group is unsubstituted or substitutedwith one or more groups Z as defined above.

An aryl group refers to a 5- to 12-membered, monovalent monocyclicaromatic group and/or monovalent polycyclic aromatic group that containsat least one aromatic carbon ring. Preferably, it is monocyclic orbicyclic. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. The group is unsubstituted or substituted witha group Z as defined above.

A saturated 5-, 6-, or 7-membered N-containing heterocyclic ring refersto a monovalent monocyclic non-aromatic ring system or monovalentpolycyclic ring system that contains at least one N and the remainingring atoms are carbon atoms. Examples of such heterocyclic ring include,but are not limited to, piperidine, piperazine, morpholine orpyrrolidine. The ring typically contains one nitrogen atom and either anadditional N atom or an O atom, or no additional heteroatoms. The ringis unsubstituted or substituted on one or more ring carbon atoms and/oron any additional N atom present in the ring. Examples of suitablesubstituents include one or more groups Z as defined above and a C₁-C₆alkyl group. When the ring is piperazine, it is typically unsubstitutedor substituted, typically on the second ring nitrogen atom, by —C(O)R,—C(O)N(R)₂ or —S(O)_(m)R, or by C₁-C₆ alkyl which is unsubstituted orsubstituted by C₁-C₆ alkoxy or OH.

An unsaturated 5- to 12-membered heterocyclic group is typicallyheteroaryl. Heteroaryl can be a 5- to 12-membered aromatic group having1, 2, 3, or 4 heteroatoms selected from O, N and S. Typically itcontains one N atom and 0, 1, 2 or 3 additional heteroatoms selectedfrom O, S and N. It may be, for example, furan, thiophene, pyrrole,indole, isoindole, pyrazole, imidazole, benzothiophene, benzothiazole,benzofuran, isoxazole, oxazole, oxadiazole, thiazole, isothiazole,thiadiazole, dihydroimidazole, pyridine, pyridine, quinoline,isoquinoline, quinoxaline, thienopyrazine, pyran, pyrimidine,pyridazine, pyrazine, triazine, triazole or tetrazole. The group can beunsubstituted or substituted with one or more groups Z as defined above.

Specific examples of the compounds of the invention include:

-   5-Ethoxy-2-(3-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0037)-   5-Ethoxy-2-(4-hydroxy-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0038)-   5-Ethoxy-2-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0039)-   2-(3-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0040)-   3-[4-(2-Dimethylamino-ethoxy)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenol    (MTR-0043)-   3-[4-(2-Dimethylamino-ethoxy)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenol    (MTR-0046)-   3-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (MTR-0047)-   2-(3,5-Difluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0053)-   5-Ethoxy-2-(1H-indol-5-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0054)-   5-Ethoxy-2-(1H-indol-6-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0055)-   2-Benzo[1,3]dioxol-5-yl-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0056)-   5-Ethoxy-2-(1H-indazol-4-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0057)-   5-Ethoxy-2-(2-fluoro-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0058)-   2-{3-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0059)-   5-Ethoxy-6-morpholin-4-yl-2-[3-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0060)-   2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0068)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0069)-   2-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0070)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0071)-   2-(3-Hydroxy-phenyl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0073)-   5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indole    (MTR-0074)-   2-(1H-Indazol-4-yl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0075)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea    (MTR-0076)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-chloro-pyridin-3-yl)-urea    (MTR-0077)-   N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-acetamide    (MTR-0078)-   2-{4-[3-(6-Chloro-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0079)-   5-Ethoxy-2-[4-(3-ethyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0081)-   [4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0083)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indazole    (MTR-0084)-   Methanesulfonic acid    3-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl    ester (MTR-0086)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0091)-   3-(4-Chloro-5-methanesulfonyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol    (MTR-0094)-   N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methane    sulfonamide (MTR-0096)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol    (MTR-0098)-   Methanesulfonic acid    4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl    ester (MTR-0100)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-thioureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0102)-   2-(4-Benzenesulfonylamino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0103)-   1-(2-Chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0108)-   5-Ethoxy-2-(4-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0111)-   5-Ethoxy-2-(4-ethylcarbamoyloxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0112)-   5-Ethoxy-6-morpholin-4-yl-2-(4-phenylcarbamoyloxy-phenyl)-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0113)-   (2-Chloro-ethyl)-carbamic acid    4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl    ester (MTR-0114)-   Benzenesulfonic acid    4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl    ester (MTR-0115)-   3-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol (MTR-0116)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (MTR-0118)-   N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-benzenesulfonamide    (MTR-0119)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid diethylamide (MTR-0120)-   5-Ethoxy-6-morpholin-4-yl-2-(4-ureido-phenyl)-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0121)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-dimethylamino-phenyl)-urea    (MTR-0123)-   1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0124)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid amide (MTR-0125)-   Phenyl-carbamic acid    4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl ester    (MTR-0127)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0128)-   1-Ethyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0129)-   Ethyl-carbamic acid    4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl ester    (MTR-0130)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-benzenesulfonamide    (MTR-0131)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-ethyl-urea    (MTR-0132)-   5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-ylamine    (MTR-0133)-   1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-phenyl-urea    (MTR-0134)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-fluoro-phenyl)-urea    (MTR-0135)-   1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-ethyl-urea    (MTR-0136)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-phenyl)-urea    (MTR-0137)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-difluoro-phenyl)-urea    (MTR-0138)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (2-morpholin-4-yl-ethyl)-amide (MTR-0139)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (2-pyrrolidin-1-yl-ethyl)-amide (MTR-0140)-   1-{4-[5-Ethoxy-4-morpholin-4-yl-6-(pyrrolidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0141)-   1-{4-[5-Ethoxy-4-morpholin-4-yl-6-(piperidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0142)-   1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea    (MTR-0143)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (2-diethylamino-ethyl)-amide (MTR-0144)-   1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0145)-   2-(6-Amino-pyridin-3-yl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0146)-   5-Ethoxy-2-{4-[3-(3-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0147)-   5-Ethoxy-6-morpholin-4-yl-2-[6-(3-phenyl-ureido)-pyridin-3-yl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0148)-   5-Ethoxy-2-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0149)-   2-{4-[3-(3,4-Difluoro-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0150)-   1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0152)-   4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (MTR-0153)-   4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0154)-   4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenol    (MTR-0155)-   5-Ethoxy-2-{6-[3-(4-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0156)-   2-{6-[3-(3,4-Difluoro-phenyl)-ureido]-pyridin-3-yl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0157)-   5-Ethoxy-2-{6-[3-(3-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0158)-   1-Ethyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0159)-   4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole    (MTR-0160)-   4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine    (MTR-0161)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0162)-   4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-benzenesulfonamide    (MTR-0163)-   1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0164)-   1-(3,4-Difluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0165)-   [2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl]-methanol    (MTR-0166)-   1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thio    urea (MTR-0167)-   1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thio    urea (MTR-0168)-   1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0169)-   4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole    (MTR-0170)-   4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine    (MTR-0171)-   1-{4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0172)-   1-{4-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0173)-   4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-1H-indazole    (MTR-0174)-   4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenylamine    (MTR-0175)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0176)-   1-(3,4-Difluoro-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0177)-   1-(4-Fluoro-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0178)-   3-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol    (MTR-0180)-   2-(4-Amino-phenyl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0181)-   5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0182)-   5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (MTR-0183)-   1-{4-[5-Methoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0184)-   1-{4-[4-(4-Methanesulfonyl-piperazine-1-carbonyl)-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0185)-   1-{4-[5-Ethoxy-4-(4-methyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea    (MTR-0186)-   [2-(4-Amino-phenyl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-acetic    acid methyl ester (MTR-0187)-   {5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-acetic    acid methyl ester (MTR-0188)-   {5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-acetic    acid (MTR-0189)-   2-{5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-acetamide    (MTR-0192)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-piperidin-1-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0193)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea    (MTR-0195)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-morpholin-4-yl-urea    (MTR-0196)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0197)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea    (MTR-0198)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(2-dimethylamino-ethoxy)-phenyl]-urea    (MTR-0199)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea    (MTR-0200)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methyl-piperazin-1-yl)-urea    (MTR-0201)-   5-Ethoxy-2-[4-(3-methyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0202)-   5-Ethoxy-2-{4-[(morpholine-4-carbonyl)-amino]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0203)-   2-{4-[3-(3-Dimethylamino-propyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0204)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0205)-   5-Ethoxy-2-{4-[3-(4-methyl-piperazin-1-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0206)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea    (MTR-0207)-   1-(3-Dimethylamino-propyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0208)-   1-(4-Methyl-piperazin-1-yl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0209)-   1-Methyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0210)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-4-morpholin-4-yl-phenyl)-urea    (MTR-0211)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoic    acid ethyl ester (MTR-0212)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0213)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (MTR-0214)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea    (MTR-0215)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thio    morpholin-4-yl-phenyl)-urea (MTR-0216)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-morpholin-4-yl-ethyl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0217)-   5-Ethoxy-6-morpholin-4-yl-2-(2-phenylamino-1H-benzoimidazol-5-yl)-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0218)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-morpholin-4-yl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0219)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-thiazol-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0220)-   5-Ethoxy-2-{4-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0221)-   5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0222)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0223)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-morpholin-4-yl-urea    (MTR-0224)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0225)-   1-(3-Fluoro-4-morpholin-4-yl-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0226)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0227)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0228)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea    (MTR-0229)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0230)-   5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0231)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-thiomorpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0232)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-morpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0233)-   2-{4-[3-(2-Amino-phenyl)-thioureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0234)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea    (MTR-0235)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea    (MTR-0236)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea    (MTR-0237)-   1-{4-[4-(4-Methyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea    (MTR-0238)-   1-(3,4-Dimethoxy-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0239)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (MTR-0240)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0241)-   1-(3-Fluoro-4-morpholin-4-yl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0242)-   2-[4-(1H-Benzoimidazol-2-ylamino)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0243)-   2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0244)-   5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylic    acid (MTR-0245)-   1-[4-(4-Methyl-piperazin-1-yl)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0246)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea    (MTR-0247)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea    (MTR-0248)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea    (MTR-0249)-   2-{4-[3-(3-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0250)-   2-{4-[3-(3-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0251)-   5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[3-(2,2,2-trifluoro-acetylamino)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0252)-   1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea    (MTR-0253)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea    (MTR-0254)-   2-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-thiophene-3-carboxylic    acid methyl ester (MTR-0255)-   1-Benzo[1,3]dioxol-5-yl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0256)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0257)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-dimethoxy-phenyl)-urea    (MTR-0258)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea    (MTR-259)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-penta-2,4-dienyl]-3-(4-methyl-piperazin-1-yl)-urea    (MTR-0260)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea    (MTR-0261)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea    (MTR-0262)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea    (MTR-0263)-   4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoic    acid ethyl ester (MTR-0264)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea    (MTR-0265)-   1-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0266)-   4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0267)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-urea    (MTR-0268)-   N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide    (MTR-0269)-   N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0270)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea    (MTR-0271)-   [4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic    acid phenyl ester (MTR-0272)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-sulfamoyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0273)-   5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0274)-   5-Ethoxy-2-(4-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0275)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(6-morpholin-4-yl-pyridin-3-yl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0276)-   2-(4-{3-[4-(2-Dimethylamino-ethylcarbamoyl)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0277)-   5-Ethoxy-2-(4-{3-[4-(morpholine-4-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0278)-   {4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-carbamic    acid phenyl ester (MTR-0279)-   1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0280)-   [4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acid    phenyl ester (MTR-0281)-   4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0282)-   4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide    (MTR-0283)-   4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine    (MTR-0284)-   1-(2-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thio    urea (MTR-0285)-   [4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0286)-   1-(2-Amino-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea    (MTR-0287)-   4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide    (MTR-0288)-   (1H-Benzoimidazol-2-yl)-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine    (MTR-0289)-   [4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic    acid phenyl ester (MTR-0290)-   1-(6-Bromo-pyridin-3-yl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0291)-   1-(2-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea    (MTR-0292)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thioureido}-benzoic    acid (MTR-0293)-   5-Ethoxy-2-(4-{3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0294)-   5-Ethoxy-2-{4-[3-(2-methoxycarbonyl-thiophen-3-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0296)-   5-Ethoxy-2-{4-[3-(1H-indazol-4-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0297)-   5-Ethoxy-2-{4-[3-(4-methyl-1H-benzotriazol-5-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0298)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0299)-   2-(4-Amino-3-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0300)-   5-Ethoxy-2-(3-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0301)-   5-Ethoxy-2-(3-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0302)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea    (MTR-0303)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea    (MTR-0304)-   (1H-Benzoimidazol-2-yl)-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine    (MTR-0305)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isopropyl-urea    (MTR-0306)-   [4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic    acid (MTR-0307)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea    (MTR-0308)-   4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine    (MTR-0309)-   (1H-Benzoimidazol-2-yl)-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine    (MTR-0310)-   5-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1H-benzoimidazol-2-ylamine    (MTR-0311)-   1-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0312)-   3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0313)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea    (MTR-0314)-   1-(3,4-Dimethoxy-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0315)-   4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoic    acid (MTR-0316)-   1-Benzo[1,3]dioxol-5-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0317)-   1-[5-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0318)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea    (MTR-0319)-   2-(4-Amino-2-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0320)-   5-Ethoxy-2-(2-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0321)-   5-Ethoxy-2-(2-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0322)-   4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0323)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea    (MTR-0324)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0325)-   4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide    (MTR-0326)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-2-fluoro-phenylamino-urea    (MTR-0327)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(5-morpholin-4-yl-pyridin-2-yl)-urea    (MTR-0328)-   1-(4-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0329)-   1-tert-Butyl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0330)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amino-urea    (MTR-0331)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenylamine    (MTR-0332)-   1-tert-Butylamino-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0333)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-urea    (MTR-0334)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea    (MTR-0335)    [4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0336)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea    (MTR-0337)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea    (MTR-0338)-   1-Isopropyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0339)-   1-(6-Bromo-pyridin-3-yl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0340)-   1-Isopropyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0341)-   1-tert-Butyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0342)-   1-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0343)-   2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-3-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0344)-   2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-2-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0345)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(1H-indazol-4-yl)-urea    (MTR-0346)-   N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide    (MTR-0347)-   1,3-Bis-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0349)-   1-(4-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0350)-   4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoic    acid (MTR-0351)-   1-(6-Bromo-pyridin-3-yl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0352)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea    (MTR-0353)-   [4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-carbamic    acid phenyl Ester (MTR-0354)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0355)    -   [4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-urea        (MTR-0356)-   4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenylamine    (MTR-0357)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide    (MTR-0358)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0359)-   4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0360)-   2-[4-(3-Benzo[1,3]dioxol-5-yl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0361)-   5-Ethoxy-2-{4-[3-(4-ethoxycarbonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0362)-   2-(4-{3-[4-(2-Dimethylamino-ethoxy)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0363)-   4-(3-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-ureido)-benzamide    (MTR-0364)-   5-Ethoxy-2-{4-[3-(4-methanesulfonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0365)-   5-Ethoxy-2-[4-(3-isopropyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0366)-   2-[4-(3-tert-Butyl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0367)-   N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0368)-   5-Ethoxy-2-{4-[3-(4-methanesulfonylamino-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0369)-   2-{4-[3-(4-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0370)-   N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0371)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea    (MTR-0372)-   6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine    (MTR-0373)-   1,3-Bis-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0374)-   3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0375)-   N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide    (MTR-0376)-   N-(3-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0377)-   1-[3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0378)-   N-(4-{3-[3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0379)    N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0380)-   1-[4-(5-Methanesulfonyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0381)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea    (MTR-0382)-   2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0383)-   3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0384)-   4-{3-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0385)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea    (MTR-0386)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-urea    (MTR-0387)-   [4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0388)-   1-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0389)-   [4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic    acid phenyl ester (MTR-0390)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0391)-   4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0392)-   N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide    (MTR-0394)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea    (MTR-0395)-   4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenylamine (MTR-0396)-   [4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acid    phenyl ester (MTR-0397)-   1-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0398)-   1-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0399)-   4-{3-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0400)-   1-[4-(5-Methanesulfinyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0401)-   2′-Amino-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylic    acid ethyl ester (MTR-0402)-   5-Ethoxy-6-morpholin-4-yl-2′-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-[2,5′]bipyrimidinyl-4-carboxylic    acid ethyl ester (MTR-0403)-   1-(4-Methanesulfonyl-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0404)-   1-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0405)-   1-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0406)-   4-{3-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0407)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea    (MTR-0408)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzamide    (MTR-0409)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzenesulfonamide    (MTR-0410)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzamide    (MTR-0411)-   4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzenesulfonamide    (MTR-0412)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea    (MTR-0413)-   N-(5-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide    (MTR-0415)-   2′-[3-(4-Carbamoyl-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylic    acid ethyl ester (MTR-0417)-   2′-[3-(4-Acetylamino-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylic    acid ethyl ester (MTR-0418)-   5-Ethoxy-2-(4-{3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0419)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea    (MTR-0420)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbon    yl)-phenyl]-urea (MTR-0421)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea    (MTR-0422)-   5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-ureido]-phenyl}-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0423)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-urea    (MTR-0424)-   5-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1,3-dihydro-benzoimidazol-2-one    (MTR-0425)-   N-(3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide    (MTR-0426)-   N-(3-Dimethylamino-propyl)-4-{3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide    (MTR-0427)-   5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine (MTR-0428)-   4-[3-(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-ureido]-benzamide    (MTR-0429)-   1-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0430)-   5-Methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine    (MTR-0431)-   4-[3-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-ureido]-benzenesulfonamide    (MTR-0432)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea    (MTR-0433)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea    (MTR-0435)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-urea    (MTR-0436)-   4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenylamine    (MTR-0437)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0438)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea    (MTR-0440)-   N-(5-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide    (MTR-0442)-   2-{4-[3-(6-Acetylamino-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic    acid ethyl ester (MTR-0443)-   N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide    (MTR-0444)-   N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-2,4-difluoro-benzenesulfonamide    (MTR-0445)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0446)-   1-[4-(5-Ethoxy-4-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0447)-   4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenylamine (MTR-0448)-   N-(4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide    (MTR-0449)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea    (MTR-0450)-   1-(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0451)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfon    yl)-phenyl]-urea (MTR-0452)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0453)-   1-[4-(Morpholine-4-carbonyl)-phenyl]-3-{4-[4-morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-urea    (MTR-0454)-   1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0455)-   4-(3-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-ureido)-benzamide    (MTR-0456)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0457)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea    (MTR-0459)-   4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0460)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea    (MTR-0461)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0462)-   N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide    (MTR-0463)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0464)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea    (MTR-0465)-   4-(5-Methylsulfanyl-2,6-di-pyridin-3-yl-pyrimidin-4-yl)-morpholine    (MTR-0466)-   N-[3-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methane    sulfonamide (MTR-0467)-   1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea    (MTR-0468)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0469)-   1-(4-Methanesulfonyl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0470)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea    (MTR-0471)-   1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0472)-   1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea    (MTR-0473)-   1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0474)-   1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0476)-   1-Ethyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0477)-   1-Methyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0478)-   1-Isopropyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0479)-   1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0480)-   1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-pyridin-4-yl-urea    (MTR-0481)-   4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine    (MTR-0482)-   4-(5-Methoxy-4-morpholin-4-yl-6-(4-aminophenyl-pyrimidin-2-yl)-phenylamine    (MTR-0483)-   1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea    (MTR-0484)-   1-Isoxazol-3-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0485)-   N-(5-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide    (MTR-0486)-   1-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0487)-   1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0488)-   1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0489)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0490)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0491)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0492)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0493)-   1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0494)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0495)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0496)-   1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0497)-   1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea    (MTR-0498)-   1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea    (MTR-0499)-   1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0500)-   1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0501)-   1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea    (MTR-0502)-   1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea    (MTR-0503)-   1-Isoxazol-3-yl-3-[4-(5-methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0504)-   1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea    (MTR-0505)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea    (MTR-0506)-   1-Isoxazol-3-yl-3-[4-(5-methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0507)-   1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea    (MTR-0508)-   1-Isoxazol-3-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-urea    (MTR-0509)    or a stereoisomer, or a tautomer, or an N-oxide, or a    pharmaceutically acceptable salt, or an ester, or a prodrug, or a    hydrate, or a solvate thereof.

The pyrimidine compounds of formula (I), or a stereoisomer, or atautomer, or an N-oxide, or a pharmaceutically acceptable salt, or anester, or a prodrug, or a hydrate, or a solvate thereof, may be preparedby any process known to be applicable to the preparation of chemicallyrelated compounds.

According to the invention, suitable pharmaceutically acceptable saltsof formula (I) include hydrochloride, hydrobromide, hydroiodide,sulfate, phosphate, mesylate, besylate, acetate, oxalate, citrate,lactate, tartrate, succinate, methanesulfonate, trifluoroacetate, andmaleate salts. The preferred salt is a hydrochloride salt. When thecompounds of the invention bear a free carboxy substituent, the saltsinclude both the above-mentioned acid addition salts and the salts ofsodium, potassium, calcium and ammonium. The latter are prepared bytreating the free pyrimidine of formula (I), or the acid addition saltthereof, with the corresponding metal base or ammonia.

The pyrimidine compounds of formula (I) may be prepared by any suitablesynthetic routes. Examples of the routes can be those set out in Schemes1 to 10 below.

In Scheme 1, R¹, R², Y and W are as defined above for formula (I). Acompound of formula (1) which is a known compound or is prepared bymethods known in the literature is converted into a compound of formula(2) by treatment with a strong base. The base is typically sodiummethoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Acompound of formula (3) is prepared by treatment of the compound offormula (2) with urea in an appropriate solvent such as ethanol.Compounds of formula (4) may be prepared by treating compounds offormula (3) with phosphorous oxychloride in the presence of anN,N-dialkylaniline. Compounds of formula (5) may be prepared by treatingcompounds of formula (4) with an amine of formula HW in an inert solventin the presence of a base. Compounds of formula (Ia) may be prepared bythe Suzuki coupling of a compound of formula (5) with a boronic acid ora boronic ester.

In Scheme 2, YR²═SCH₃, Z═Cl or Br, W and R¹ are as defined above forformula (I). Compounds of formula (6) may be prepared by treatingBarbituric acid with dimethyl sulfoxide. Compounds of formula (7) may beprepared by treating compounds of formula (6) with phosphorousoxychloride or phosphorous oxybromide in the presence of anN,N-dialkylaniline. Compounds of formula (8) may be prepared by treatingcompounds of formula (7) with an amine of formula HW in an inert solventin the presence of a base. Compounds of formula (I) may be prepared bythe Suzuki coupling of a compound of formula (8) with a boronic acid ora boronic ester.

In Scheme 3, YR²═SCH₃, W and R¹ are as defined above for formula (I).The compound of formula (3) wherein YR²═SCH₃ is prepared from5-Iodouracil according to the method in Organic Letters, 2007, 9, 1639.Compounds of formula (4) may be prepared by treating compounds offormula (3) with phosphorous oxychloride in the presence of anN,N-dialkylaniline. Compounds of formula (5) may be prepared by treatingcompounds of formula (4) with an amine of formula HW in an inert solventin the presence of a base. Compounds of formula (Ia) may be prepared bythe Suzuki coupling of a compound of formula (5) with a boronic acid ora boronic ester.

In Scheme 4, YR²═—OCH₃ or —OEt, Z═—C(O)NR₃R₄, R¹ and W are as definedabove for formula (I). A compound of formula (9), which is a knowncompound or is prepared by methods known in the literature, is convertedinto a compound of formula (10) by treatment with a strong base. Thebase is typically sodium methoxide, sodium ethoxide, potassium methoxideor potassium ethoxide. A compound of formula (11) is prepared bytreatment of the compound of formula (10) with urea in an acidsolution 1. Compounds of formula (11) may be converted to compounds offormula (12) in the presence of a base solution. Compounds of formula(13) may be prepared by the acetylation of a compound of formula (12)with a acetyl chloride. Compounds of formula (14) may be prepared bytreating compounds of formula (13) with phosphorous oxychloride in thepresence of an N,N-dialkylaniline. Compounds of formula (15) may beprepared by treating compounds of formula (14) with an amine of formulaHW in an inert solvent in the presence of a base. Compounds of formula(16) may be prepared by the Suzuki coupling of a compound of formula(15) with a boronic acid or a boronic ester. Compounds of formula (17)can be obtained by hydrolysis of compounds of formula (16). Compounds offormula (I) can be prepared by coupling of compounds of formula (17)with an amine by one of the standard methods of amide bond formation.

In Scheme 5, YR²=—OCH₃ or —OEt, Z=—CH₂NR₃R₄, R¹ and W are as definedabove for formula (I). Compounds of formula (18) can be obtained fromcompounds of formula (15) by treatment with sodium borohydride or otherreducing agent. Dess-Martin periodinate or other oxidizing agent is usedto oxidize compounds of formula (18) to compounds of formula (19).Reductive amination of compounds of formula (19) using the appropriateamine and sodium triacetoxyborohydride proceeds smoothly to yieldcompounds of formula (20). Compounds of formula (I) may be prepared bythe Suzuki coupling of a compound of formula (20) with a boronic acid ora boronic ester.

In Scheme 6, YR²═SCH₃, Z=—CH₂C(O)NR₃R₄, R¹ and W are as defined abovefor formula (I). Compounds of formula (7) may be prepared by the methodof scheme 2. Compounds of formula (21) may be prepared by reactingtogether compounds of formula (7) and sodium methoxide in MeOH.Compounds of formula (22) may be prepared by reacting together compoundsof formula (21) and dimethyl malonate in the presence of sodium hydride.Compounds of formula (23) can be obtained by demethylation anddecarboxylation of compounds of formula (22) in the presence of anexcess of alkali hydroxide. Compounds of formula (24) may be prepared bytreating compounds of formula (23) with phosphorous oxychloride orphosphorous oxybromide in the presence of an N,N-dialkylaniline.Compounds of formula (25) may be prepared by treating compounds offormula (24) with an amine of formula HW in an inert solvent in thepresence of a base. Compounds of formula (26) may be prepared by theSuzuki coupling of a compound of formula (25) with a boronic acid or aboronic ester. Compounds of formula (27) can be obtained by hydrolysisof compounds of formula (26). Compounds of Formula (I) can be preparedby coupling of compounds of formula (27) with an amine by one of thestandard methods of amide bond formation.

In Scheme 7, R₇═OMe, OEt, YR²═OCH₃, OEt, Z═Cl, Br, R¹ and W are asdefined above for formula (I). Compounds of formula (30) are preparedfrom carbonic acid diethyl ester (28, R₇=OEt) according to the method inJ. of Heterocyclic Chemistry, 1989, 1261-1271 or from compounds offormula (29) according to the method in J. Med. Chem., 1974, 1197.Compounds of formula (6) are prepared by treating the compounds offormula (30) with urea in an appropriate solvent such as ethanol.Compounds of formula (7) may be prepared by treating compounds offormula (6) with phosphorous oxychloride in the presence of anN,N-dialkylaniline. Compounds of formula (8) may be prepared by treatingcompounds of formula (7) with an amine of formula HW in an inert solventin the presence of a base. Compounds of formula (I) may be prepared bythe Suzuki coupling of a compound of formula (8) with a boronic acid ora boronic ester.

In Scheme 8, R₇═OMe, OEt, YR²═OCH₃, OEt, Z═Cl, Br, W is as defined abovefor formula (I). The use of diverse amidines in the cyclization reactionwith substituted 1,3-dicarbony compound can obtain pyrimidines bearing acarbon-carbon linkage in position 2. The desired amidines are eithercommercially available or can be obtained from known procedures by oneskilled in the art. Compounds of formula (31) or (35) may be prepared bytreating appropriate amidine with 1,3-dicarbony compound (2) or (30).Compounds of formula (32) or (36) may be prepared by treating compoundsof formula (31) or (35) with phosphorous oxychloride in the presence ofan N,N-dialkylaniline. Compounds of formula (33) or (37) may be preparedby treating compounds of formula (32) or (36) with an amine of formulaHW in an inert solvent in the presence of a base. Compounds of formula(34) or (38) may be prepared by the reduction of compounds of formula(33) or (37) with a hydrogen/palladium on carbon.

Substitution at the 4-Cl is not limited to an amino group, as describedin Scheme 1-8. 4-Cl can also bear a carbon linker. In Scheme 9, R², Y, W(Wa, Wb), R₈═NR₃R₄ are as defined above for formula (I). Each chlorineatom of the compound of formula (4) is selectively replaced at differentconditions. Compounds of formula (4) are reacted with different amines(Wa=morpholine or substituted morpholine derivatives) to yield thecompound of formula (5a) and with aryl and heteroaryl boronic acid(ester) (Wb) by Suzuki coupling in the presence of palladium catalyst toyield the compound of formula (5b). The second chlorine atom is replacedwith 4-aminoaryl and aminoheteroaryl boronic acid(ester) in the presenceof palladium catalyst to yield (Ia) and (Ib) respectively. The aminogroup is converted to the urea derivatives by three different proceduresdepending upon the availability of the starting material. Some of theexamples shown here are converted into the urea derivatives by reacting(Ia) or (Ib) with an appropriately substituted isocyanate orthioisocyanate derivative. Some of the urea derivatives reported hereare prepared by reacting (Ia) or (Ib) with triphosgene in presence oftiethylamine and an appropriately substituted primary amine derivative.The corresponding carbamate derivatives are prepared by reacting (Ia),(Ib) or a substituted amine derivative with a phenyl chloroformatereagent. The phenyl N-substituted carbamates are reacted with differentsubstituted amine, heteroalkyl amine or heteroaryl aniline to yield thecompound of formula (Ia-a) or (Ib-b).

Substitution at the 6-Cl is not limited to an amino group, as describedin Scheme 2, 7 and 8. 6-Cl can also bear an oxygen or a carbon linker.In Scheme 10, R², Y, W(Wa, Wb, Wc) and R₈=NR₃R₄ are as defined above forformula (I). Each chlorine atom of the compound of formula (7) isselectively replaced at different conditions. Substitution at thechlorine position is not limited to an amino group. Chlorine positioncan also bear an oxygen or a carbon linker. 2,4,6-Trisubstitutedpyrimidines can be obtained via standard procedure (i.e. SNAr,Mitsunobu, Suzuki, Stille and Heck couplings). Compounds of formula (7)are reacted with different amines (Wa=morpholine or substitutedmorpholine derivatives) to yield the compound of formula (8a) and witharyl and heteroaryl boronic acid (ester) (Wb) by Suzuki coupling in thepresence of palladium catalyst to yield the compound of formula (8b).The second chlorine atom is replaced with 4-aminoaryl andaminoheteroaryl boronic acid(ester) in the presence of palladiumcatalyst to yield (Ic) and (Id) respectively. The third chlorine atom isreplaced with alkyl, alkene, alkyne, aryl or heteroaryl byorganomagnesium or organozinc or organoboronic ester reagents to yield(Ic-c) and (Id-d) respectively. The amino group of (Ic-c) and (Id-d) isconverted to the urea derivatives by three different procedures asdescribed above (Scheme 9) to yield the compound of formula (Ic-c-c) and(Id-d-d). Compounds of formula (8a) and (8b) also are reacted withdifferent amines and alcohols to give (le), (If), (Ie), and (Ih),respectively. Compounds of formula (Ie), (If), (Ig) and (Ih) thenunderwent the same procedures as described above to yield compounds offormula (Ie-e-e), (If-f-f), (Ig-g-g) and (Ih-h-h).

It has now been found that a series of novel pyrimidine compounds haveinhibitory activity against the PI3K enzymes and the class IV kinasemTOR. It is now well understood that deregulation of oncogenes andtumour-suppressor genes contributes to the formation of malignanttumours, for example, by way of increased cell proliferation orincreased cell survival. It is also now known that signaling pathwaysmediated by the PI3K/mTOR families have a central role in a number ofcell processes, including proliferation and survival, and deregulationof these pathways is a causative factor in a wide spectrum of humancancers and other diseases.

The compounds of the present invention have been found to be inhibitorsof mTOR kinase and PI3 kinase. The pharmacological inhibitors of mTORkinase and PI3 kinase should be of therapeutic value for treatment ofvarious forms of cancer comprising solid tumors such as carcinomas,sarcomas, leukaemias and lymphoid malignancies. Accordingly, a compoundof the present invention can be used to treat a disease or disorderarising from abnormal cell growth, function or behaviour associated withmTOR kinase and PI3 kinase.

Also within the scope of this invention are a pharmaceutical compositionthat contains an effective amount of at least one of the pyrimidinecompounds of formula (I) or a stereoisomer, or a tautomer, or anN-oxide, or a pharmaceutically acceptable salt, or an ester, or aprodrug, or a hydrate, or a solvate thereof together with apharmaceutically acceptable carrier, a method for treating a PI3Kkinase-/mTOR kinase-related disease (e.g., cancer) by administering to asubject in need of this treatment an effective amount of the pyrimidinecompounds of formula (I), and a method of decreasing the activity of atleast one PI3K kinase and mTOR kinase by contacting the at least onePI3K kinase and mTOR kinase with at least one of the pyrimidinecompounds of formula (I).

As used herein, the term “PI3 kinase-/mTOR kinase-related disease”refers to a disease or condition that is characterized by abnormal PI3and/or mTOR activity or a disease or condition that can be treated withchanges to the activity of at least one of PI3 and mTOR. Abnormal PI3and/or mTOR activity can arise as the result of elevated PI3 and/or mTORexpression level, or presence of PI3 and/or mTOR expression that doesnot occur in normal conditions. PI3 kinase-/mTOR kinase-related diseasesdescribed herein include, but are not limited to, cancer, diabetes,immune disorders, hyper-proliferation disorders, hyperproliferativedisorders of the kidney, renal disease, von Hippel-Lindau disease,restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis,inflammatory disorders, immunological disorders such as autoimmunediseases (e.g., AIDS, lupus, etc.), cardiovascular disorders (e.g.atherosclerosis), and blood vessel proliferative disorders such asabnormal vasculogenesis.

The term “treating” refers to administering a pyrimidine compound offormula (I) to a subject that has a PI3 kinase-/mTOR kinase-relateddisease, or has a symptom of or a predisposition toward it, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve, affect or reduce the risk of the disorder, or the symptoms ofor the predisposition toward the disorder. For example, treating cancerrefers to treatment resulting in inhibition of cancer growth or cancercell growth, regression in cancer growth (i.e. reducing the size of adetectable cancer), or disappearance of a cancer. The term “an effectiveamount” refers to the amount of the active agent that is required toconfer the intended therapeutic effect in the subject. Effective amountsmay vary, as recognized by those skilled in the art, depending on routeof administration, the excipient used, and the possibility of co-usagewith other agents. The subject in need of the treatment can be a mammal.The term “mammal” refers to human or nonhuman mammal, for example, dogs,cats, pigs, cows, sheep, goats, horses, rats, or mice.

Cancer that can be treated by the methods of the invention is anyabnormal cell or tissue growth, for example, a tumor, whether malignant,pre-malignant, or non-malignant. It is characterized by uncontrolledproliferation of cells that may or may not invade the surrounding tissueand, hence, may or may not metastasize to new body sites. Cancerencompasses carcinomas, which are cancers of epithelial cells;carcinomas include squamous cell carcinomas, adenocarcinomas, melanomas,and hepatomas. Cancer also encompasses sarcomas, which are tumors ofmesenchymal origin; sarcomas include osteogenic sarcomas, leukemias, andlymphomas. Cancers may involve one or more neoplastic cell type. Theterm cancer includes, as non-limiting examples, lung cancer, coloncancer, colorectal cancer, breast cancer, prostate cancer, liver cancer,pancreatic cancer, bladder cancer, gastric cancer, renal cancer,salivary gland cancer, ovarian cancer, uterine body cancer, cervicalcancer, oral cancer, skin cancer, brain cancer, lymphoma, and leukemia.The cancers also include Epidermal Growth Factor Receptor (EGFR)dependent cancers or cancers that resist to EGFR targeting agent.

The compounds described herein can be administered to a mammal inconjunction with radiation therapy, immunotherapy, monoclonal antibodytherapy, hormonal therapy, chemotherapy using other agents, and/orsurgery. “In conjunction with” means that the therapies do not need tooccur at the same time, and can be in succession, or alternate with eachother and/or periods of rest and recovery.

In one embodiment, a PI3 kinase-/mTOR kinase-related disease, such ascancer, can be treated with a method comprising administering aneffective amount of at least a pyrimidine compound of formula (I) and atleast one chemotherapeutic agent to a mammal. Non-limiting examples ofchemotherapeutic agent include protein kinase inhibitors other than thecompound described herein (e.g., imatinib mesylate, gefitinib,dasatinib, erlotinib, lapatinib, sunitinib, nilotinib, and sorafenib;antibodies, including, e.g., trastuzumab, rituximab, cetuximab, andbevacizumab; mitoxantrone; dexamethasone; prednisone; and temozolomide),alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa,ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine,and cyclophosphamide), mitotic inhibitors, antimetabolites (e.g.,capecitibine, gemcitabine, 5-fluorouracil or 5-fluorouracil/leucovorin,fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, andmethotrexate), cell cycle inhibitors, enzymes, hormones, anti-hormones,growth-factor inhibitors, plant alkaloids and terpenoids, topoisomeraseinhibitors (e.g., etoposide, teniposide, camptothecin, topotecan,irinotecan, doxorubicin, and daunorubicin), antitumor antibiotics (e.g.,actinomycin D, bleomycin, mitomycin C, adriamycin, daunorubicin,idarubicin, doxorubicin and pegylated liposomal doxorubicin), vincaalkaloids (e.g., vincristine and vinblastin), taxanes (e.g., paclitaxeland docetaxel), platinum agents (e.g., cisplatin, carboplatin, andoxaliplatin), thalidomide and related analogs (e.g., CC-5013 andCC-4047), monoclonal antibodies, antiangiogenic agents, and combinationsthereof.

To practice the method of this invention, the above-describedpharmaceutical composition can be administered orally, parenterally, byinhalation spray, topically, rectally, nasally, buccally, vaginally orvia an implanted reservoir. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional, and intracranial injection or infusion techniques. In oneembodiment, the pharmaceutical composition of this invention isadministered intravenously. The pharmaceutically acceptable carriers mayinclude, but are not limited to, water, Ringer's solution, isotonicsodium chloride solution or phosphate buffered saline, and solutionscontaining thickening and solubilizing agents, such as glucose,polyethylene glycol, and polypropylene glycol and mixtures thereof.

A sterile injectable composition can be formulated according totechniques known in the art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent. Among the acceptable vehicles andsolvents that can be employed are mannitol, water, Ringer's solution andisotonic sodium chloride solution. Fatty acids, such as oleic acid andits glyceride derivatives, are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions can also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agents.Other commonly used surfactants such as Tweens or Spans or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms can also be used for purposes of formulation.

A composition for oral administration can be any orally acceptabledosage form including, but not limited to, capsules, tablets, emulsionsand aqueous suspensions, dispersions and solutions. In the case oftablets for oral use, carriers that are commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsor emulsions are administered orally, the active ingredient can besuspended or dissolved in an oily phase combined with emulsifying orsuspending agents. If desired, certain sweetening, flavoring, orcoloring agents can be added. A nasal aerosol or inhalation compositioncan be prepared according to techniques well known in the art ofpharmaceutical formulation. The composition of the present invention mayalso be administered in the form of suppositories for rectaladministration.

Suitable in vitro assays can be used to preliminarily evaluate theefficacy of the pyrimidine compounds of formula (I) in anticanceractivities such as inhibiting growth of tumor cells. The compounds canfurther be examined for their efficacy in treating cancer. For example,a compound can be administered to an animal (e.g., a mouse model) havingcancer and its therapeutic effects then assessed. Based on the results,an appropriate dosage range and administration route can also bedetermined.

The invention will be further described in the Examples as follows. Theexamples given below are intended to be illustrative only and not tolimit the invention. Any modifications and variations that can be easilymade by those skilled in the art fall within the scope of the disclosureof the specification and the appended claims of the present invention.

EXAMPLES Example 1 Preparation of Compounds of Formula (I) in Scheme 42-Ethoxy-Malonic Acid Diethyl Ester

A mixture of diethyl oxalate (39.23 ml, 1.12 eq.) and ethylethoxyacetate (34.95 ml, 1 eq.) was added dropwise to a slurry of sodiumethoxide (18.64 g, 1.07 eq.) in toluene (100 ml) at 45-50° C. Afterdropping, the resulting solution was heated to 70-80° C. for 2 hrs andpoured into 70 ml of 14% HCl with cooling. The resultant mixture wasextracted with EA and the combined organic layers were washed with brineand dried in vacuo to give 55.86 g (93.7%) of a product.

2-Methoxy-Malonic Acid Diethyl Ester

A mixture of diethyl oxalate (27.5 ml, 1 eq.) and methyl methoxyacetate(20 ml, 1 eq.) was added dropwise to a slurry of sodium methoxide (16.4g, 1.5 eq.) in toluene (350 ml) at 45-50° C. After dropping, theresulting solution was heated to 70-80° C. for 2 hrs and poured into 70ml of 14% HCl with cooling. The resultant mixture was extracted with EAand the combined organic layers were washed with brine and dried invacuo to give 16.7 g (40.5%) of a product.

(2,5-Dioxo-imidazolidin-4-ylidene)-ethoxy-acetic acid ethyl ester

A mixture of diethyl 2-ethoxy-3-oxo-succinate (55.86 g, 1 eq) and urea(14.41 g, 1 eq.) was refluxed for 2.5 h in 1 M HCl-AcOH (1200 ml, 5 eq.)and allowed to become cool. The cooled mixture was evaporated todryness. The residues were dissolved in MeOH, heated aside forcrystallization. After crystallization, the precipitates were filteredto give a product which was an off-white solid (15.11 g, 27.5%).

¹H NMR (500 MHz, DMSO-d₆): δ1.21-1.27 (m, 6H), 3.82-3.86 (m, 2H),4.24-4.29 (m, 2H), 9.79 (s, 1H), 11.33 (s, 1H)

(2,5-Dioxo-imidazolidin-4-ylidene)-methoxy-acetic acid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.28 (m, 3H), 3.61 (s, 3H), 4.25-4.29(m, 2H), 9.85 (s, 1H), 11.39 (s, 1H)

5-Ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid

(2,5-dioxo-imidazolidin-4-ylidene)-ethoxy-acetic acid ethyl ester (16.02g, 1 eq.) was dissolved in aq. 1 N KOH (281 ml, 4 eq.) and refluxed for3.5 hrs. The mixture was cooled to 0° C. and carefully acidified withconc. HCl. After overnight cooling (4° C.), it led to the formation ofwhite precipitate. The mixture was filtered and the precipitate wasdried in vacuo. The product obtained was a white solid (7.76 g, 55%).

¹H NMR (500 MHz, DMSO-d₆): δ1.17-1.23 (m, 3H), 3.89-3.93 (m, 2H), 10.60(s, 1H), 11.42 (s, 1H)

2,6-Dihydroxy-5-methoxy-pyrimidine-4-carboxylic acid

¹H NMR (500 MHz, DMSO-d₆): δ3.61 (s, 3H), 10.53 (s, 1H), 11.39 (s, 1H)

5-Ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester

Acetyl chloride (100 ml, 36 eq.) was added dropwise to absolute EtOH(780 ml) at 0° C. After stirring the resulting solution for 20 min atr.t., 5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid (7.76 g, 1eq.) was added in one portion and the mixture was refluxed overnight.The volatiles were evaporated in vacuo to give5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester as anoff-white solid (8.85 g, 100%).

¹H NMR (500 MHz, DMSO-d₆): δ1.18-1.30 (m, 6H), 3.91-3.95 (m, 2H),4.25-4.31 (m, 2H), 10.74 (s, 1H), 11.51 (s, 1H)

5-Methoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.30 (m, 3H), 365 (s, 3H), 4.27-4.32(m, 2H), 10.80 (s, 1H), 11.54 (s, 1H)

2,6-Dichloro-5-ethoxy-pyrimidine-4-carboxylic acid ethyl ester

N,N-dimethylaniline (6.85 ml) was added to a stirred solution of5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester (8.85 g)in POCl₃ (265 ml) and the mixture was refluxed overnight. Excess POCl₃was evaporated in vacuo and the residue was poured into ice-water andextracted with ether. The combined ethereal layers were washed withbrine, dried and evaporated in vacuo. Purification by flashchromatography gave a product (8.33 g, 81%).

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.35 (m, 3H), 4.13-4.18 (m, 2H),4.39-4.43 (m, 2H)

2,6-Dichloro-5-methoxy-pyrimidine-4-carboxylic acid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.26-1.35 (m, 3H), 3.93 (s, 3H), 4.40-4.48(m, 2H)

2-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethylester

2,6-dichloro-5-ethoxy-pyrimidine-4-carboxylic acid ethyl ester (2 g, 1eq.) was stirred in toluene (80 ml) and a solution of morpholine (0.73ml, 1.1 eq.) in toluene (20 ml) was added dropwise in about 10 minutesat −10˜0° C., after stirring the resulting solution for 3 h at r.t.Water was added and extracted with EA. The combined organic layers werewashed with brine, dried and evaporated in vacuo. Purification by flashchromatography gave a product (1.79 g, 75%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.41 (m, 6H), 3.76-3.78 (m, 4H),3.87-3.89 (m, 4H), 3.92-3.96 (m, 2H), 4.39-4.43 (m, 2H)

2-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethylester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.38-1.42 (m, 3H), 3.74 (s, 3H), 3.77-3.79(m, 4H), 3.87-3.89 (m, 4H), 4.40-4.44 (m, 2H)

5-Ethoxy-2-(3-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

A mixture of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylicacid ethyl ester (152 mg, 1 eq.),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (137.9 mg, 1.3eq.), dioxane (6 ml), H₂O (1 ml), Pd(PPh₃)₄ (56 mg, 0.1 eq.) and sodiumcarbonate (102 mg, 2 eq.) was heated to reflux overnight. The solventwas removed in vacuo. The residue was extracted with EA, and the organiclayer washed with brine and dried. The crude was purified bychromatography to give a product (99.6 mg, 55%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.36-1.39 (m, 3H), 1.44-1.46 (m, 3H),3.85-3.87 (m, 4H), 3.91-3.93 (m, 4H), 3.99-4.03 (m, 2H), 4.46-4.50 (m,2H), 6.94-6.95 (m, 1H), 7.27-7.33 (m, 1H), 7.82-7.83 (m, 1H), 7.91-7.92(m, 1H)

Compounds of the following Examples were synthesized following thesynthetic method described above. The bronic acids or bronic esters arereadily recognizable by one skilled in the art and are commerciallyavailable from Aldrich, Acros Organics and Maybridge Chemical CompanyLtd.

5-Ethoxy-2-(4-hydroxy-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.82-3.88 (m, 8H), 3.96-3.99 (m, 5H), 4.47-4.49 (m, 2H), 5.84 (s, 1H),6.94-6.96 (m, 1H), 7.89-7.91 (m, 2H)

5-Ethoxy-2-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.82-3.84 (m, 4H), 3.88-3.89 (m, 4H), 3.95 (s, 3H), 3.94-4.00 (m, 2H),4.44-4.49 (m, 2H), 6.96-6.99 (m, 1H), 8.04-8.11 (m, 2H)

2-(3-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.36 (m, 3H), 1.42-1.44 (m, 3H), 3.74(s, 2H), 3.81-3.84 (m, 4H), 3.88-3.90 (m, 4H), 3.96-4.00 (m, 2H),4.44-4.49 (m, 2H), 6.75-6.76 (m, 1H), 7.20-7.26 (m, 1H), 7.68-7.74 (m,1H)

2-(3,5-Difluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.35-1.38 (m, 3H), 1.43-1.46 (m, 3H),3.83-3.84 (m, 4H), 3.89-3.91 (m, 4H), 3.98-4.02 (m, 2H), 4.45-4.50 (m,2H), 6.84-6.88 (m, 1H), 7.84-7.86 (m, 2H)

5-Ethoxy-2-(1H-indol-6-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic acidethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.37 (m, 3H), 1.43-1.46 (m, 3H),3.84-3.86 (m, 4H), 3.91-3.93 (m, 4H), 3.98-4.02 (m, 2H), 4.46-4.50 (m,2H), 6.57 (s, 1H), 7.26-7.28 (m, 1H), 7.65-7.66 (m, 1H), 8.13-8.14 (m,1H), 8.33 (s, 1H), 8.45 (s, 1H)

5-Ethoxy-2-(1H-indol-5-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic acidethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.37 (m, 3H), 1.43-1.46 (m, 3H),3.84-3.86 (m, 4H), 3.91-3.93 (m, 4H), 3.97-4.02 (m, 2H), 4.46-4.50 (m,2H), 6.63 (s, 1H), 7.21-7.22 (m, 1H), 7.39-7.41 (m, 1H), 8.23-8.28 (m,2H), 8.67 (s, 1H)

5-Ethoxy-2-(1H-indazol-4-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.37-1.40 (m, 3H), 1.46-1.49 (m, 3H),3.87-3.88 (m, 4H), 3.93-3.95 (m, 4H), 4.03-4.07 (m, 2H), 4.48-4.52 (m,2H), 7.45-7.48 (m, 1H), 7.58-7.59 (m, 1H), 8.21-8.22 (m, 1H), 8.98 (s,1H)

2-Benzo[1,3]dioxol-5-yl-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.82-3.83 (m, 4H), 3.87-3.88 (m, 4H), 3.95-3.99 (m, 2H), 4.44-4.48 (m,2H), 6.00 (s, 1H), 6.84-6.86 (m, 1H), 7.81 (s, 1H), 7.92-7.94 (m, 1H)

5-Ethoxy-2-(2-fluoro-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.35-1.38 (m, 3H), 1.41-1.44 (m, 3H),3.79-3.80 (m, 4H), 3.90-3.92 (m, 4H), 3.98-4.03 (m, 2H), 4.43-4.47 (m,2H), 7.00-7.04 (m, 1H), 7.10-7.13 (m, 1H), 7.57-7.59 (m, 1H)

2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.32-1.35 (m, 3H), 1.42-1.44 (m, 3H),3.82-3.87 (m, 10H), 3.94-3.99 (m, 2H), 4.43-4.48 (m, 2H), 6.68-6.70 (m,2H), 8.15-8.16 (m, 2H)

5-Methoxy-2-(3-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.44-1.47 (m, 3H), 3.81 (s, 3H), 3.86-3.88(m, 4H), 3.91-3.93 (m, 4H), 4.47-4.51 (m, 2H), 5.33 (s, 1H), 6.94-6.95(m, 1H), 7.29-7.34 (m, 1H), 7.82-7.83 (m, 1H), 7.91-7.93 (m, 1H)

5-Methoxy-2-(1H-indazol-4-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.45-1.48 (m, 3H), 3.83 (s, 3H), 3.87-3.87(m, 4H), 3.92-3.94 (m, 4H), 4.48-4.53 (m, 2H), 7.44-7.47 (m, 1H),7.58-7.60 (m, 1H), 8.20-8.21 (m, 1H), 8.98 (m, 1H)

2-(4-hydroxy-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.41-1.43 (m, 3H),3.82-3.84 (m, 4H), 3.86-3.89 (m, 4H), 3.95-3.99 (m, 2H), 4.43-4.47 (m,2H), 5.79 (s, 1H), 6.84-6.86 (m, 2H), 8.21-8.22 (m, 2H)

2-(6-Amino-pyridin-3-yl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.81-3.83 (m, 4H), 3.87-3.88 (m, 4H), 3.95-3.99 (m, 2H), 4.44-4.48 (m,2H), 4.67 (s, 2H), 6.51-6.52 (m, 1H), 8.34-8.36 (m, 1H), 9.01-9.02 (m,1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

Phenyl isocyanate (0.22 ml, 1.5 eq.) was added to a stirred solution of2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (500 mg, 1 eq.) in toluene (25 ml) and the mixture wasreacted for 4 h at 80° C. The reaction mixture was cooled, the solventwas removed in vacuo, and the residue was washed with EA and filtered togive a product (550 mg, 83%).

¹H NMR (500 MHz, Acetone-d₆): δ1.31-1.40 (m, 6H), 3.81-3.83 (m, 4H),3.88-3.90 (m, 4H), 3.98-4.03 (m, 2H), 4.39-4.43 (m, 2H), 6.98-7.01 (m,1H), 7.27-7.30 (m, 2H), 7.54-7.56 (m, 2H), 7.62-7.64 (m, 2H), 8.17 (s,1H), 8.27-8.29 (m, 2H), 8.33 (s, 1H)

5-Ethoxy-2-[4-(3-ethyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

Ethyl isocyanate (0.012 ml, 1.4 eq.) was added to a stirred solution of2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (40 mg, 1 eq.) in toluene (2 ml) and the mixture wasreacted overnight at 80° C.

The reaction mixture was extracted with EA, washed with brine. The crudewas purified by chromatography to give a product (12 mg, 25.2%).

¹H NMR (500 MHz, Acetone-d₆): δ1.10-1.13 (m, 3H), 1.31-1.39 (m, 6H),3.25 (m, 2H), 3.81-3.82 (m, 4H), 3.86-3.87 (m, 4H), 4.00-4.01 (m, 2H),4.39-4.41 (m, 2H), 5.85 (m, 1H), 7.55-7.57 (m, 2H), 8.09 (s, 1H),8.21-8.23 (m, 2H)

The urea compounds of the following Examples were synthesized followingthe synthetic method described above by the different isocycanate thatare commercially available.

2-{3-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.35 (m, 3H), 1.38-1.41 (m, 3H),3.81-3.83 (m, 4H), 3.89-3.91 (m, 4H), 4.02-4.05 (m, 2H), 4.40-4.44 (m,2H), 7.38-7.41 (m, 1H), 7.55-7.57 (m, 1H), 7.76-7.79 (m, 1H), 7.82-7.84(m, 2H), 8.01-8.03 (m, 1H), 8.16-8.17 (m, 1H), 8.36 (s, H), 8.43 (s,1H), 8.58 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[3-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.34 (m, 3H), 1.38-1.41 (m, 3H),3.81-3.83 (m, 4H), 3.89-3.91 (m, 4H), 4.02-4.05 (m, 2H), 4.41-4.44 (m,2H), 6.99 (m, 1H), 7.26-7.30 (m, 2H), 7.55-7.57 (m, 2H), 7.84-7.86 (m,1H), 7.98-8.00 (m, 1H), 8.15 (s, 1H), 8.27 (s, 1H), 8.34-8.36 (m, 1H)

2-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.33-1.42 (m, 6H), 3.83-3.85 (m, 4H),3.90-3.92 (m, 4H), 4.03-4.05 (m, 2H), 4.41-4.45 (m, 2H), 7.58-7.60 (m,1H), 7.64-7.66 (m, 2H), 7.78-7.80 (m, 1H), 8.18 (m, 1H), 8.31-8.32 (m,2H), 8.52 (s, 1H), 8.63 (s, 1H)

5-Ethoxy-2-{4-[3-(3-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.34 (m, 3H), 1.37-1.40 (m, 3H),3.81-3.83 (m, 4H), 3.88-3.90 (m, 4H), 4.00-4.02 (m, 2H), 4.40-4.42 (m,2H), 6.70-6.80 (m, 1H), 7.10-7.20 (m, 1H), 7.21-7.31 (m, 1H), 7.62-7.64(m, 3H), 8.28-8.30 (m, 2H), 8.38 (s, 2H)

5-Ethoxy-2-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.30-1.35 (m, 3H), 1.38-1.41 (m, 3H),3.81-3.84 (m, 4H), 3.88-3.90 (m, 4H), 4.01-4.04 (m, 2H), 4.40-4.44 (m,2H), 7.06-7.10 (m, 2H), 7.56-7.64 (m, 4H), 8.22-8.34 (m, 3H)

2-{4-[3-(3,4-Difluoro-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.30-1.35 (m, 3H), 1.38-1.41 (m, 3H),3.82-3.84 (m, 4H), 3.89-3.91 (m, 4H), 4.00-4.04 (m, 2H), 4.40-4.44 (m,2H), 7.20-7.25 (m, 2H), 7.62-7.64 (m, 2H), 7.80-7.90 (m, 1H), 8.29-8.30(m, 2H), 8.38 (s, 1H)

2-{4-[3-(6-Chloro-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.31-1.40 (m, 6H), 3.80-3.82 (m, 4H),3.88-3.90 (m, 4H), 4.00-4.03 (m, 2H), 4.39-4.43 (m, 2H), 7.37-7.39 (m,1H), 7.62-7.64 (m, 2H), 8.11-8.13 (m, 1H), 8.28-8.30 (m, 2H), 8.47-8.49(m, 1H)

5-Ethoxy-6-morpholin-4-yl-2-(4-ureido-phenyl)-pyrimidine-4-carboxylicacid ethyl ester

Trimethylsilyl isocyanate (0.1 ml, 5 eq.) was added to a stirredsolution of2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (60 mg, 1 eq.) in THF (2 ml) and the mixture wasreacted to reflux overnight. The reaction mixture was extracted with EAand washed with brine. The crude was purified by chromatography to givea product (26.2 mg, 40%).

¹H NMR (500 MHz, Acetone-d₆): δ1.31-1.40 (m, 6H), 3.80-3.82 (m, 4H),3.86-3.88 (m, 4H), 3.99-4.02 (m, 2H), 4.38-4.42 (m, 2H), 5.55 (s, 2H),7.57-7.59 (m, 2H), 8.22-8.24 (m, 2H), 8.31 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[6-(3-phenyl-ureido)-pyridin-3-yl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆) δ1.33-1.36 (m, 3H), 1.39-1.41 (m, 3H),3.82-3.84 (m, 4H), 3.92-3.94 (m, 4H), 4.02-4.04 (m, 2H), 4.42-4.44 (m,2H), 7.00-7.10 (m, 1H), 7.31-7.34 (m, 3H), 8.55-8.65 (m, 1H), 8.90-9.00(s, 1H), 9.24-9.25 (m, 1H), 11.40 (s, 1H)

5-Ethoxy-2-{6-[3-(4-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.41 (m, 6H), 3.82-3.84 (m, 4H),3.92-3.94 (m, 4H), 4.02-4.05 (m, 2H), 4.41-4.45 (m, 2H), 7.08-7.12 (m,2H), 7.35-7.36 (m, 1H), 7.71-7.73 (m, 2H), 8.59-8.61 (m, 1H), 8.97 (s,1H), 9.23-9.24 (m, 1H), 11.51 (s, 1H)

2-{6-[3-(3,4-Difluoro-phenyl)-ureido]-pyridin-3-yl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.33-1.41 (m, 6H), 3.82-3.83 (m, 4H),3.92-3.93 (m, 4H), 4.00-4.05 (m, 2H), 4.41-4.45 (m, 2H), 7.25-7.38 (m,3H), 7.89-7.92 (m, 1H), 8.60-8.62 (m, 1H), 9.06 (s, 1H), 9.24 (s, 1H),11.78 (s, 1H)

5-Ethoxy-2-{6-[3-(3-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.41 (m, 6H), 3.82-3.84 (m, 4H),3.92-3.94 (m, 4H), 4.00-4.05 (m, 2H), 4.41-4.45 (m, 2H), 6.79-6.82 (m,1H), 7.33-7.38 (m, 3H), 7.73-7.75 (m, 1H), 8.60-8.63 (m, 1H), 9.03 (s,1H), 9.26 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-thioureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

Phenyl isothiocyanate (0.02 ml, 1.5 eq.) was added to a stirred solutionof 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (40 mg, 1 eq.) in CHCl₃ (3 ml) and the mixture wasreacted overnight at r.t. The reaction mixture was extracted with EA andwashed with brine. The crude was purified by chromatography to give aproduct (32.6 mg, 60%).

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.40 (m, 6H), 3.81-3.83 (m, 4H),3.89-3.91 (m, 4H), 4.01-4.04 (m, 2H), 4.39-4.43 (m, 2H), 7.16-7.19 (m,1H), 7.35-7.38 (m, 2H), 7.55-7.57 (m, 2H), 7.67-7.70 (m, 2H), 8.30-8.32(m, 2H), 9.19 (s, 1H), 9.23 (s, 1H)

2-(4-Benzenesulfonylamino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

Phenyl sulfonyl chloride (0.02 ml, 1.3 eq.), Et₃N (1 drop) was added toa stirred solution of2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (40 mg, 1 eq.) in CH₂Cl₂ (2 ml) and the mixture wasreacted overnight at r.t. The reaction mixture was extracted with EA andwashed with brine. The crude was purified by chromatography to give aproduct (13 mg, 23.7%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.40-1.44 (m, 3H),3.81-3.87 (m, 8H), 4.10-4.14 (m, 2H), 4.43-4.47 (m, 2H), 6.79 (s, 1H),7.12-7.13 (m, 2H), 7.41-7.44 (m, 2H), 7.51-7.53 (m, 1H), 7.77-7.79 (m,2H), 8.20-8.22 (m, 2H)

5-Ethoxy-2-(4-ethylcarbamoyloxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

Ethyl isocyanate (0.013 ml, 1.5 eq.) was added to a stirred solution of2-(4-hydroxy-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (40 mg, 1 eq.) in toluene (3 ml) and the mixture wasreacted to reflux overnight. The reaction mixture was extracted with EAand washed with brine. The crude was purified by chromatography to givea product (12 mg, 25.2%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.23-1.27 (m, 3H), 1.34-1.37 (m, 3H),1.39-1.45 (m, 3H), 3.31-3.34 (m, 2H), 3.82-3.83 (m, 4H), 3.88-3.89 (m,4H), 3.96-4.11 (m, 2H), 4.44-4.49 (m, 2H), 5.07 (s, 1H), 7.17-7.19 (m,2H), 8.31-8.33 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-(4-phenylcarbamoyloxy-phenyl)-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, Acetone-d₆): δ1.32-1.40 (m, 6H), 3.81-3.83 (m, 4H),3.90-3.92 (m, 4H), 4.02-4.05 (m, 2H), 4.40-4.44 (m, 2H), 7.07-7.10 (m,1H), 7.30-7.37 (m, 4H), 7.62-7.64 (m, 2H), 8.39-8.40 (m, 2H), 9.28 (s,1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid amide

5-ethoxy-6-4-morpholin-yl-2-[(3-4-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (50 mg, 1 eq.), 7N NH₃/MeOH (9 ml) and THF (0.5 ml)were placed in high pressure reacted bottle and reacted to reflux for 2days. The reaction mixture was cooled, solvent removed in vacuo, and theresidue washed with heating MeOH and filtered to give a product (37.7mg, 80%).

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 3.75-3.76 (m, 4H),3.80-3.81 (m, 4H), 3.92-3.96 (m, 2H), 6.97-6.99 (m, 1H), 7.27-7.31 (m,2H), 7.46-7.47 (m, 2H), 7.54-7.55 (m, 2H), 7.60 (s, 1H), 7.95 (s, 1H),8.21-8.3 (m, 2H), 8.70 (s, 1H), 8.90 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid

1N KOH (10.5 ml, 5 eq.) was added to a stirred solution of5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (1.03 g, 1 eq.) in MeOH (10 ml) and the mixture wasrefluxed for 4 h. The mixture was cooled to 0° C. and carefullyacidified with conc. HCl. The mixture was filtered and the precipitatewas dried in vacuo, and a product was obtained as a white solid (0.93 g,97%).

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 3.75-3.76 (m, 4H),3.81-3.82 (m, 4H), 3.90-3.95 (m, 2H), 6.96-6.99 (m, 1H), 7.27-7.30 (m,2H), 7.46-7.48 (m, 2H), 7.55-7.57 (m, 2H), 8.17-8.19 (m, 2H), 9.09 (s,1H), 9.29 (s, 1H)

Potassium salt of5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid

1N KOH (5 ml, 5 eq.) was added to a stirred solution of5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (500 mg, 1 eq.) in MeOH (5 ml) and the mixture wasrefluxed for 4 h. The mixture was cooled to r.t. and filtered. Theprecipitate was washed with MeOH and dried in vacuo, and a product wasobtained as a white solid (400 mg, 78%).

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.26 (m, 3H), 3.74 (m, 8H), 4.01-4.03(m, 2H), 6.94-6.95 (m, 1H), 7.25-7.28 (m, 2H), 7.55-7.57 (m, 2H),7.69-7.70 (m, 2H), 8.19-8.20 (m, 2H), 10.17 (s, 1H), 10.30 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid diethylamide

EDC (50 mg, 1.5 eq.), HOBT (40 mg, 1.5 eq.), Et₂NH (0.0275 ml, 1.5 eq.)and Et3N (0.05 ml, 2.0 eq.) were added to a stirred solution of5-ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (80 mg, 1 eq.) in dry DMF (2 ml) and the mixture reacted overnightat r.t. The mixture was quenched with H₂O, extracted with EA, and washedwith brine. The crude was purified by chromatography to give a product(43 mg, 48%).

¹H NMR (500 MHz, DMSO-d₆): δ1.07-1.10 (m, 3H), 1.15-1.18 (m, 3H),1.22-1.24 (m, 3H), 3.14-3.16 (m, 2H), 3.45-3.46 (m, 2H), 3.76-3.81 (m,4H), 3.87-3.90 (m, 4H), 4.02-4.03 (m, 2H), 6.98-6.99 (m, 1H), 7.27-7.30(m, 2H), 7.45-7.47 (m, 2H), 7.54-7.56 m, 2H), 8.17-8.19 (m, 2H), 8.71(s, 1H), 8.90 (s, 1H)

1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.27 (m, 3H), 3.28-3.30 (m, 2H),3.56-3.57 (m, 2H), 3.67 (m, 4H), 3.76-3.82 (m, 8H), 3.90-3.91 (m, 2H),6.98 (m, 1H), 7.28-7.31 (m, 2H), 7.46-7.47 (m, 2H), 7.54-7.56 (m, 2H),8.17-8.18 (m, 2H), 8.71 (s, 1H), 8.90 (s, 1H)

1-{4-[5-Ethoxy-4-morpholin-4-yl-6-(pyrrolidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.21-1.24 (m, 3H), 1.84-1.88 (m, 4H),3.25-3.27 (m, 2H), 3.47-3.49 (m, 2H), 3.75-3.81 (m, 8H), 3.90-3.91 (m,2H), 6.98 (m, 1H), 7.29-7.30 (m, 2H), 7.45-7.47 (m, 2H), 7.53-7.55 (m,2H), 8.16-8.18 (m, 2H), 8.70 (s, 1H), 8.90 (s, 1H)1-{4-[5-Ethoxy-4-morpholin-4yl-6-(piperidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.26 (m, 3H), 1.50-1.64 (m, 6H), 3.20(m, 2H), 3.62 (m, 2H), 3.76-3.80 (m, 8H), 3.87-3.91 (m, 2H), 6.97-6.99(m, 1H), 7.27-7.30 (m, 2H), 7.45-7.47 (m, 2H), 7.53-7.55 (m, 2H),8.16-8.18 (m, 2H), 8.76 (s, 1H), 8.95 (s, 1H)

1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.27 (m, 3H), 2.95 (s, 3H), 3.13 (m,2H), 3.23 (m, 2H), 3.40 (m, 2H), 3.77-3.82 (m, 10H), 3.88-3.92 (m, 2H),6.98 (m, 1H), 7.27-7.30 (m, 2H), 7.46-7.47 (m, 2H), 7.54-7.55 (m, 2H),8.17-8.19 (m, 2H), 8.71 (s, 1H), 8.91 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid(2-morpholin-4-yl-ethyl)-amide

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.27 (m, 6H), 2.36-2.63 (m, 6H),3.3-3.41 (m, 4H), 3.59-3.60 (m, 4H), 3.74-3.75 (m, 4H), 3.81-3.82 (m,4H), 3.92-3.95 (m, 2H), 6.97-6.99 (m, 1H), 7.27-7.30 (m, 2H), 7.46-7.48(m, 2H), 7.54-7.56 (m, 2H), 8.22-8.24 (m, 2H), 8.54-8.57 (m, 1H), 8.70(s, 1H), 8.91 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.27 (m, 6H), 1.70 (m, 4H), 2.57-2.60(m, 4H), 3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.90-3.95 (m, 2H),6.96-6.99 (m, 1H), 7.27-7.30 (m, 2H), 7.47-7.49 (m, 2H), 7.56-7.57 (m,2H), 8.20-8.22 (m, 2H), 8.55-8.57 (m, 1H), 9.10 (s, 1H), 9.30 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (2-diethylamino-ethyl)-amide

¹H NMR (500 MHz, DMSO-d₆): δ0.98-1.01 (m, 6H), 1.24-1.27 (m, 3H),2.54-2.58 (m, 8H), 3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.92-3.95 (m,2H), 6.98 (m, 1H), 7.27-7.30 (m, 2H), 7.46-7.48 (m, 2H), 7.55-7.56 (m,2H), 8.21-8.23 (m, 2H), 8.50 (m, 1H), 9.00 (s, 1H), 9.20 (s, 1H)

5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.42-1.44 (m, 3H), 3.76 (s, 3H), 3.81-3.873(m, 8H), 4.45-4.50 (m, 2H), 7.05-7.07 (m, 1H), 7.12 (s, 1H), 7.22 (m,1H), 7.27-7.33 (m, 4H), 7.37-7.39 (m, 2H), 8.20-8.21 (m, 2H)

5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid

¹H NMR (500 MHz, DMSO-d₆): δ3.72 (s, 3H), 3.77-3.82 (m, 8H), 6.99-7.00(m, 1H), 7.28-7.30 (m, 2H), 7.46-7.48 (m, 2H), 7.55-7.57 (m, 2H),8.18-8.19 (m, 2H), 8.78 (s, 1H), 8.98 (s, 1H)

1-{4-[5-Methoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ3.28 (m, 2H), 3.33 (m, 4H), 3.56 (m, 2H),3.67-3.68 (m, 7H), 3.76-3.82 (m, 8H), 6.98-6.99 (m, 1H), 7.28-7.30 (m,2H), 7.46-7.47 (m, 2H), 7.54-7.56 (m, 2H), 8.17-8.19 (m, 2H), 8.71 (s,1H), 8.91 (s, 1H)

1-{4-[4-(4-Methanesulfonyl-piperazine-1-carbonyl)-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d6): δ2.95 (s, 3H), 3.12 (m, 2H), 3.24 (m, 2H),3.39 (m, 2H), 3.68 (s, 3H), 3.77-3.82 (m, 10H), 6.97-6.99 (m, 1H),7.27-7.30 (m, 2H), 7.46-7.47 (m, 2H), 7.54-7.56 (m, 2H), 8.17-8.19 (m,2H), 8.71 (s, 1H), 8.91 (s, 1H)

1-{4-[5-Ethoxy-4-(4-methyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.23-1.27 (m, 6H), 2.20 (s, 3H), 2.29 (m,2H), 2.37-2.38 (m, 2H), 3.24-3.26 (m, 2H), 3.65 (m, 2H), 3.76-3.81 (m,8H), 3.87-3.91 (m, 2H), 6.97-6.99 (m, 1H), 7.27-7.30 (m, 2H), 7.46-7.47(m, 2H), 7.54-7.56 (m, 2H), 8.16-8.18 (m, 2H), 8.731 (s, 1H), 8.93 (s,1H)

5-Ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylicacid ethyl ester

Phenyl chloroformate (0.95 ml, 1.5 eq.) was added to a stirred solutionof 2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (1.15 g, 1 eq.) in EA (20 ml) and NaHCO₃ (sat) (20 ml).The mixture was reacted at room temperature for 2 hrs. The reactionmixture was diluted with NaHCO₃ (sat) and extracted with EA. The organicsolution was washed with brine, was dried (MgSO₄), filtered andconcentrated under reduced pressure to give a crude carbamate (1.21 g,80%).

5-Ethoxy-2-[4-(3-methyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

2M Methyl amine (1.1 ml, 10 eq.) was added to a stirred solution of5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (110 mg, 1 eq.) in dioxane (3 ml), and the mixture wasreacted at 80° C. overnight. The reaction mixture was concentrated andpurified by flash chromatography to give a product (47.5 mg, 50%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.35 (m, 3H), 1.40-1.43 (m, 3H),2.73-2.75 (m, 3H), 3.81-3.82 (m, 4H), 3.86-3.87 (m, 4H), 3.94-3.98 (m,2H), 4.43-4.48 (m, 2H), 5.25 (s, 1H), 7.2 (s, 1H), 7.36-7.37 (m, 2H),8.21-8.22 (m, 2H)

5-Ethoxy-2-{4-[(morpholine-4-carbonyl)-amino]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

Morpholine (0.071 ml, 4 eq.) was added to a stirred solution of5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (100 mg, 1 eq.) and Et₃N (0.085 ml, 3 eq.) in dioxane(3 ml), the mixture was reacted at 80° C. overnight. The reactionmixture was concentrated, and purified by flash chromatography to give aproduct (59 mg, 60%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.44 (m, 3H),3.49-3.51 (m, 4H), 3.74-3.75 (m, 4H), 3.83-3.84 (m, 4H), 3.87-3.88 (m,4H), 3.95-3.99 (m, 2H), 4.44-4.48 (m, 2H), 6.45 (s, 1H), 7.42-7.43 (m,2H), 8.26-8.28 (m, 2H)

The urea compounds of the following examples were synthesized followingthe synthetic method described above by the appropriate amine with5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylicacid ethyl ester.

2-{4-[3-(3-Dimethylamino-propyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.41-1.44 (m, 3H),1.66-1.69 (m, 2H), 2.20-2.22 (s, 6H), 2.39-2.41 (m, 2H), 3.34 (s, 2H),3.81-3.83 (m, 4H), 3.87-3.89 (m, 4H), 3.96-3.99 (m, 2H), 4.43-4.47 (m,2H), 7.40-7.42 (m, 2H), 8.24-8.26 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.27 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.93 (m, 2H), 4.35-4.40 (m,2H), 7.32-7.34 (m, 1H), 7.56-7.58 (m, 2H), 7.95-7.97 (m, 1H), 8.17-8.21(m, 3H), 8.61 (s, 1H), 8.91 (s, 1H), 9.01 (s, 1H)

5-Ethoxy-2-{4-[3-(4-methyl-piperazin-1-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

4-methyl-piperazin-1-ylamine (0.52 ml, 2 eq.) was added to a stirredsolution of5-ethoxy-6-morpholin-4-yl-2-(4-phenoxycarbonylamino-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (100 mg, 1 eq.) and Et₃N (0.085 ml, 3 eq.) in dioxane(3 ml), the mixture was reacted at 80° C. overnight. The reactionmixture was concentrated, and purified by flash chromatography to give aproduct (49.2 mg, 45%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.32-1.35 (m, 3H), 1.41-1.44 (m, 3H), 2.34(s, 3H), 2.46-2.49 (m, 4H), 3.54-3.56 (m, 4H), 3.81-3.83 (m, 4H),3.87-3.88 (m, 4H), 4.10-4.12 (m, 2H), 4.44-4.46 (m, 2H), 6.67 (s, 1H),7.41-7.43 (m, 2H), 8.24-8.25 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-morpholin-4-yl-ethyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.41-1.44 (m, 3H), 2.48(s, 4H), 2.52-2.54 (m, 2H), 3.36-3.38 (m, 2H), 3.70 (s, 4H), 3.82-3.83(m, 4H), 3.87-3.89 (m, 4H), 3.96-3.99 (m, 2H), 4.43-4.47 (m, 2H), 5.34(s, 1H), 7.39-7.41 (m, 2H), 8.26-8.28 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-morpholin-4-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.35 (m, 3H), 1.41-1.44 (m, 3H),3.49-3.51 (m, 4H), 3.74-3.75 (m, 4H), 3.81-3.83 (m, 4H), 3.87-3.88 (m,4H), 3.95-3.99 (m, 2H), 4.43-4.48 (m, 2H), 6.50 (s, 1H), 7.41-7.43 (m,2H), 8.25-8.27 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-thiazol-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.93 (m, 2H), 4.35-4.40 (m,2H), 7.13 (s, 1H), 7.38-7.39 (m, 1H), 7.58-7.60 (m, 2H), 8.19-8.21 (m,2H), 9.21 (s, 1H)

5-Ethoxy-2-{4-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),2.99-3.01 (m, 4H), 3.82-3.84 (m, 4H), 3.85 (m, 4H), 3.87-3.88 (m, 4H),3.95-3.99 (m, 2H), 4.45-4.50 (m, 2H), 6.81-6.84 (m, 1H), 6.94-6.97 (m,2H), 7.07 (s, 1H), 7.17-7.20 (m, 1H), 7.35-7.37 (m, 2H), 8.21-8.23 (m,2H)

5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.70-3.71 (m, 2H), 3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.93 (m,2H), 3.96 (m, 2H), 4.18 (m, 2H), 4.35-4.40 (m, 2H), 7.29-7.31 (2H),7.48-7.50 (m, 2H), 7.55-7.57 (m, 2H), 8.17-8.18 (m, 2H), 8.24 (s, 1H),8.97 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.80-3.81 (m, 4H), 3.86 (m, 4H), 3.94-3.98 (m, 2H), 4.47-4.51 (m, 2H),7.20-7.22 (m, 1H), 7.29-7.32 (m, 3H), 7.53-7.55 (m, 3H), 7.70 (s, 1H),8.11-8.12 (m, 2H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.76(m, 4H), 3.82-3.83 (m, 4H), 3.91-3.92 (m, 2H), 4.38-4.39 (m, 2H), 7.04(m, 1H), 7.53-7.54 (m, 1H), 7.62-7.63 (m, 2H), 7.77 (m, 1H), 8.19-8.20(m, 2H), 8.30 (m, 1H), 9.49 (s, 1H), 10.68 (s, 1H)

5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.21-1.24 (m, 3H), 1.28-1.31 (m, 3H), 2.17(s, 3H), 2.41 (m, 4H), 3.01 (s, 4H), 3.71 (m, 4H), 3.77 (m, 4H),3.86-3.87 (m, 2H), 4.33-4.34 (m, 2H), 6.83-6.85 (m, 2H), 7.25-7.27 (m,2H), 7.48-7.50 (m, 2H), 8.10-8.12 (m, 2H), 8.43 (s, 1H), 8.81 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-thiomorpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H),2.67-2.69 (m, 4H), 3.38-3.40 (m, 4H), 3.01 (m, 4H), 3.75-3.76 (m, 4H),3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m, 2H), 6.88-6.89 (m,2H), 7.31-7.32 (m, 2H), 7.53-7.55 (m, 2H), 8.15-8.16 (m, 2H), 8.48 (s,1H), 8.85 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-morpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.01-3.03 (m, 4H), 3.72-3.75 (m, 8H), 3.81-3.82 (m, 4H), 3.89-3.93 (m,2H), 4.36-4.40 (m, 2H), 6.88-6.90 (m, 2H), 7.31-7.32 (m, 2H), 7.52-7.54(m, 2H), 8.15-8.16 (m, 2H), 8.47 (s, 1H), 8.84 (s, 1H)

2-{4-[3-(2-Amino-phenyl)-thioureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

To a stirred solution of 1,1-thiocarbonyldiimidazole (216.5 mg, 1.5eq.), imidazole (164.52 mg, 3 eq.) and CH₃CN (10 ml) at 0° C.,2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (300 mg, 1 eq.) dissolved in CH₃CN (10 ml) was addeddropwise over 10 min. After 10 min, the cooling bath was removed. After3 h, benzene-1,2-diamine (175.2 mg, 2 eq.) was added and the reactionwas heated to 50° C. for 3 h, and then stirred at ambient temperaturefor 16 h. The solvent was removed by evaporation. The residue waschromatographed to give a thiourea (120 mg, 29%)

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m,2H), 6.56-6.59 (m, 1H), 6.75-6.76 (m, 1H), 6.96-6.99 (m, 1H), 7.09-7.10(m, 1H), 7.68-7.69 (m, 2H), 8.17-8.19 (m, 2H), 9.17 (s, 1H), 9.82 (s,1H)

2-[4-(1H-Benzoimidazol-2-ylamino)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

A solution of thiourea (120 mg, 1 eq.) in THF (5 ml) and DCC (56.85 mg,1.2 eq.) was heated under reflux with stirring for 4 h. The cooledsolution was stirred overnight and filtered to give a product (33.7 mg,30%).

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.77 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m,2H), 7.00-7.03 (m, 2H), 7.30-7.32 (m, 2H), 7.37-7.39 (m, 2H), 7.85-7.86(m, 2H), 8.20-8.21 (m, 2H), 9.76 (s, 1H), 11.00 (s, 1H)

2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.76(m, 4H), 3.81-3.82 (m, 4H), 3.91-3.92 (m, 2H), 4.36-4.40 (m, 2H), 7.21(m, 1H), 7.52-7.58 (m, 4H), 7.82-7.84 (m, 3H), 8.18-8.19 (m, 2H), 8.99(s, 1H), 9.05 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid

¹H NMR (500 MHz, DMSO-d₆): δ1.26-1.28 (m, 3H), 3.75-3.76 (m, 4H),3.81-3.82 (m, 4H), 3.91-3.95 (m, 2H), 4.37-4.39 (m, 2H), 7.56-7.60 (m,2H), 7.89 (m, 1H), 8.18-8.23 (m, 2H), 8.32-8.34 (m, 1H), 8.48-8.49 (m,1H), 9.08 (m, 1H), 9.77 (s, 1H), 10.23 (s, 1H)

2-{4-[3-(3-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.04(s, 3H), 3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H),4.36-4.40 (m, 2H), 7.17-7.21 (m, 3H), 7.54-7.56 (m, 2H), 7.79 (m, 1H),8.16-8.18 (m, 2H), 8.76 (s, 1H), 8.85 (s, 1H), 9.94 (s, 1H)

2-{4-[3-(3-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.90-3.92 (m, 2H), 4.37-4.38 (m,2H), 7.35 (m, 2H), 7.47-7.48 (m, 1H), 7.56-7.58 (m, 2H), 7.63-7.64 (m,1H), 7.91-7.94 (m, 2H), 9.17-8.19 (m, 2H), 8.86 (s, 1H), 8.99 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[3-(2,2,2-trifluoro-acetylamino)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H),2.67-2.69 (m, 4H), 3.38-3.40 (m, 4H), 3.01 (m, 4H), 3.75-3.76 (m, 4H),3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m, 2H), 7.57-7.59 (m,3H), 7.72-7.74 (m, 1H), 7.84-7.85 (m, 1H), 8.18-8.20 (m 2H), 8.58 (s,1H), 9.11 (s, 1H), 9.27 (s, 1H)

1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.27 (m, 3H), 3.28-3.29 (m, 2H),3.55-3.57 (m 2H), 3.66 (m, 4H), 3.76 (m, 4H), 3.81 (m, 4H), 3.88-3.92(m, 2H), 7.32-7.35 (m, 1H), 7.55-7.57 (m, 2H), 7.95-7.97 (m, 1H),8.17-8.21 (m, 3H), 8.61-8.62 (m, 1H), 8.95 (s, 1H), 9.10 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-sulfamoyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m,2H), 7.22 (s, 1H), 7.56-7.58 (m, 2H), 7.62-7.63 (m, 2H), 7.73-7.75 (m,2H), 8.18-8.19 (m, 2H), 9.12 (s, 1H), 9.18 (s, 1H)

2-{4-[3-(4-Carboxy-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl-ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m,2H), 7.56 (m, 4H), 7.86-7.88 (, 2H), 8.16-8.18 (m, 2H), 9.26 (s, 1H),9.33 (s, 1H)

5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

EDC (53.7 mg, 1.5 eq.), HOBT (42.9 mg, 1.5 eq.), 1-methyl-piperazine(0.03 ml, 1.5 eq.) and Et₃N (0.053 ml, 2.0 eq.) were added to a stirredsolution of2-{4-[3-(4-carboxy-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (80 mg, 1 eq.) in dry DMF (2 ml) and the mixturereacted overnight at r.t. The mixture was quenched with H₂O, extractedwith EA, and washed with brine. The crude was purified by chromatographyto give a product (34.5 mg, 30%).

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.19(s, 3H), 2.31 (m, 4H), 3.50 (m, 4H), 3.75-3.76 (m, 4H), 3.82 (m, 4H),3.89-3.93 (m, 2H), 4.35-4.40 (m, 2H), 7.32-7.34 (m, 2H), 7.52-7.57 (m,4H), 8.16-8.18 (m 2H), 9.27 (s, 1H), 9.29 (s, 1H).

5-Ethoxy-2-(4-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.22(s, 3H), 2.42 (m, 4H), 3.40 (m, 4H), 3.75-3.76 (m, 4H), 3.81-3.82 (m,4H), 3.89-3.92 (m, 2H), 4.35-4.39 (m, 2H), 6.81-6.82 (m, 1H), 7.53-7.54(m, 2H), 7.69-7.70 (m, 1H), 8.14-8.16 (m, 3H), 8.52 (s, 1H), 8.99 (s,1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(6-morpholin-4-yl-pyridin-3-yl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.71(m, 4H), 3.75 (m, 4H), 3.82 (m, 4H), 3.89-3.91 (m, 2H), 4.35-4.40 (m,2H), 6.82-6.84 (m, 1H), 7.53-7.55 (m, 2H), 7.72-7.74 (m, 1H), 8.15-8.18(m, 3H), 8.51 (s, 1H), 8.96 (s, 1H)

2-(4-{3-[4-(2-Dimethylamino-ethylcarbamoyl)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.17(s, 6H), 2.37-2.39 (m, 2H), 3.75-3.76 (m, 4H), 3.82 (m, 4H), 3.89-3.93(m, 2H), 4.35-4.40 (m, 2H), 7.54-7.59 (m 4H), 7.77-7.79 (m, 2H),8.16-8.18 (m, 3H), 9.5 (b, 2H)

5-Ethoxy-2-(4-{3-[4-(morpholine-4-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.50(m, 4H), 3.59 (m, 4H), 3.75-3.76 (m, 4H), 3.82 (m, 4H), 3.89-3.93 (m,2H), 4.35-4.40 (m, 2H), 7.35-7.38 (m, 2H), 7.52-7.57 (m, 4H), 8.17-8.18(m, 2H), 8.95 (s, 1H), 8.99 (s, 1H)

{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-carbamicacid phenyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.27 (m, 3H), 3.28-3.30 (m, 2H),3.55-3.57 (m, 2H), 3.66 (s, 4H), 3.75-3.76 (m, 4H), 3.80-3.82 (m, 2H),3.88-3.92 (m, 2H), 7.24-7.29 (m, 3H), 7.42-7.46 (m, 2H), 7.60-7.62 (m,2H), 8.20-8.22 (m, 2H), 10.45 (s, 1H)

1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.27 (m, 3H), 3.29 (m, 2H), 3.56 (m,2H), 3.67-3.69 (m, 6H), 3.75-3.96 (m, 12H), 4.18 (s, 2H), 7.28-7.30 (m2H), 7.47-7.50 (m, 2H), 7.54-7.56 (m, 2H), 8.16-8.18 (m, 2H), 8.80 (s,1H), 8.94 (s, 1H)

5-Ethoxy-2-(4-{3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.22(s, 3H), 2.46 (m, 4H), 3.10 (s, 4H), 3.75-3.76 (m, 4H), 3.81-3.83 (m,4H), 3.89-3.93 (m, 2H), 4.35-4.39 (m, 2H), 7.44-7.46 (m, 2H), 7.59-7.60(m, 2H), 7.96 (s, 1H), 8.17-8.19 (m, 2H), 9.21 (s, 1H), 10.5 (b, 1H)

5-Ethoxy-2-{4-[3-(2-methoxycarbonyl-thiophen-3-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.83-3.88 (m, 11H), 3.96-4.00 (m, 2H), 4045-4.49 (m, 2H), 7.19 (m, 1H),7.46-7.51 (m, 3H), 8.05 (s, 1H), 8.29-8.31 (m, 2H), 9.72 (s, 1H)

5-Ethoxy-2-{4-[3-(1H-indazol-4-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.92 (m, 2H), 4.36-4.40 (m,2H), 7.14-7.16 (m, 1H), 7.25-7.28 (m, 1H), 7.60-7.61 (m, 2H), 7.66-7.67(m, 1H), 8.13 (s, 1H), 8.19-8.21 (m, 2H), 8.99 (s, 1H), 9.12 (m, 1H),13.1 (s, 1H)

5-Ethoxy-2-{4-[3-(4-methyl-1H-benzotriazol-5-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H), 2.38(s, 3H), 3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.92 (m, 2H),4.36-4.40 (m, 2H), 7.24-7.26 (m, 1H), 7.60-7.62 (m, 2H), 7.67-7.69 (m,1H), 8.17-8.18 (m, 2H), 8.57 (s, 1H), 9.44 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H) 1.32-1.35 (m, 3H),3.75-6.76 (m, 4H) 3.82-3.83 (m, 4H), 3.89-3.92 (m, 2H), 4.36-4.40 (m,2H), 6.90-6.93 (m, 1H), 7.17-7.19 (m, 1H), 7.49 (s, 1H), 7.54 (m, 2H),8.15-8.17 (m, 2H), 8.82 (s, 1H), 8.95 (s, 1H)

2-(4-Amino-3-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.30-1.33 (m, 3H), 1.39-1.42 (m, 3H),3.79-3.80 (m, 4H), 3.83-3.84 (m, 4H), 3.92-3.94 (m, 4H), 4.42-4.44 (m,2H), 6.75 (m, 1H), 7.93-7.94 (m, 2H)

5-Ethoxy-2-(3-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.82-3.84 (m, 4H), 3.88-3.90 (m, 4H), 3.96-4.00 (m, 2H), 4.44-4.48 (m,2H), 7.20-7.22 (m, 4H), 7.26-7.27 (m, 1H), 7.39-7.42 (m, 2H), 8.09-8.15(m, 3H)

5-Ethoxy-2-(3-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.70(m, 2H), 3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.89-3.92 (m, 2H),3.93-3.96 (m, 2H), 4.18 (s, 2H), 4.36-4.40 (m, 2H), 7.30-7.32 (m, 2H),7.48-7.49 (m, 2H), 7.98-8.04 (m, 2H), 8.29-8.32 (m, 1H), 8.80 (s, 1H),9.22 (s, 1H)

2-(4-Amino-2-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.32-1.35 (m, 3H), 1.39-1.42 (m, 3H),3.79-3.80 (m, 4H), 3.85-3.87 (m, 4H), 3.94-3.99 (m, 4H), 4.41-4.46 (m,2H), 6.37-6.39 (m, 1H), 6.45-6.47 (m, 1H), 7.89-7.92 (m, 1H)

5-Ethoxy-2-(2-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 1.42-1.45 (m, 3H),3.82-3.84 (m, 4H), 3.88-3.90 (m, 4H), 3.96-4.00 (m, 2H), 4.44-4.48 (m,2H), 7.13-7.14 (m, 2H), 7.18-7.20 (m, 2H), 7.39-7.48 (m, 3H), 8.04-8.07(m, 1H)

5-Ethoxy-2-(2-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.30-1.33 (m, 3H),3.69-3.80 (m, 10H), 3.89-3.97 (m, 4H), 4.18 (s, 2H), 4.34-4.39 (m, 2H),7.19-7.21 (m, 1H), 7.29-7.31 (m, 2H), 7.47-7.49 (m, 2H), 7.55-7.58 (m,1H), 7.91 (m, 1H), 8.88 (s, 1H), 9.13 (s, 1H)

2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-3-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.28 (m, 3H), 1.32-1.35 (m, 3H),3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.89-3.93 (m, 2H), 4.36-4.40 (m,2H), 7.21 (m, 1H), 7.51-7.53 (m, 2H), 7.85-7.85 (m, 3H), 7.99-8.05 (m,3H), 8.29-8.32 (m, 1H), 8.87 (s, 1H), 9.39 (s, 1H)

2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-2-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.30-1.33 (m, 3H),3.73-3.74 (m, 10H), 3.79-3.80 (m, 4H), 3.90-3.94 (m, 2H), 4.34-4.38 (m,2H), 7.21-7.22 (m, 2H), 7.59 (m, 3H), 7.82-7.84 (m, 3H), 7.93-7.96 (m,1H), 9.05 (s, 1H), 9.20 (s, 1H)

2-[4-(3-Benzo[1,3]dioxol-5-yl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.75(m, 4H), 3.82 (m, 4H), 3.90-3.91 (m, 4H), 4.37-4.38 (m, 2H), 5.98 (s,2H), 6.77 (m, 1H), 6.83 (m, 1H), 7.21 (s, 1H), 7.52-7.53 (m, 2H),8.15-8.17 (m, 2H), 8.60 (s, 1H), 8.87 (s, 1H)

5-Ethoxy-2-{4-[3-(4-ethoxycarbonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.29-1.33 (m, 6H), 3.75(m, 4H), 3.82 (m, 4H), 3.90-3.91 (m, 4H), 4.37-4.38 (m, 2H), 5.98 (s,2H), 7.55-7.60 (m, 4H), 7.88-7.90 (m, 2H), 8.17-8.19 (m, 2H), 9.06 (s,1H), 9.15 (s, 1H)

2-(4-{3-[4-(2-Dimethylamino-ethoxy)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.29-1.33 (m, 3H), 2.20(s, 6H), 2.59 (m, 2H), 3.75 (m, 4H), 3.82 (m, 4H), 3.90-3.91 (m, 4H),3.99-4.03 (m, 2H), 4.37-4.38 (m, 2H), 6.86 (m, 2H), 7.35-7.37 (m, 0.86(m, 2H), 7.35-7.37 (m, 2H), 7.53-7.55 (m, 2H), 8.14-8.16 (m, 2H), 8.71(s, 1H), 9.04 (s, 1H)

4-(3-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-ureido)-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 3.28 (m, 2H), 3.56 (m,2H), 3.67 (m, 4H), 3.75 (m, 4H), 3.82 (m, 4H), 3.88-3.92 (m, 2H), 7.19(m, 1H), 7.51-7.56 (m, 4H), 7.81-7.83 (m, 3H), 8.17-8.19 (m, 2H), 8.98(s, 1H), 9.02 (s, 1H)

5-Ethoxy-2-{4-[3-(4-methanesulfonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.28 (m, 3H), 1.32-1.35 (m, 3H), 3.16(s, 3H), 3.75-3.76 (m, 4H), 3.82-3.83 (m, 4H), 3.90-3.93 (m, 2H),4.35-4.39 (m, 2H), 7.56-7.58 (m, 2H), 7.69-7.71 (m, 2H), 7.82 (m, 2H),8.18-8.19 (m, 2H), 9.10 (m, 1H), 9.25 (s, 1H)

5-Ethoxy-2-[4-(3-isopropyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.14-1.15 (m, 6H), 1.32-1.35 (m, 3H),1.41-1.43 (m, 3H), 3.81-3.82 (m, 4H), 3.87 (m, 4H), 3.94-3.99 (m, 2H),4.44-4.47 (m, 2H), 4.83-4.85 (m, 1H), 6.77 (s, 1H), 7.34-7.36 (m, 2H),8.22-8.24 (m, 2H)

2-[4-(3-tert-Butyl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ1.32-1.36 (m, 12H), 1.41-1.44 (m, 3H),3.81-3.82 (m, 4H), 3.86-3.87 (m, 4H), 3.94-3.99 (m, 2H), 4.44-4.47 (m,2H), 4.77 (m, 1H), 6.46 (m, 1H), 7.31-7.33 (m, 2H), 8.22-8.24 (m, 2H)

5-Ethoxy-2-{4-[3-(4-methanesulfonylamino-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.26-1.27 (m, 3H), 1.32-1.34 (m, 3H), 2.92(s, 3H), 3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.88-3.93 (m, 2H),4.35-4.39 (m, 2H), 7.14-7.16 (m, 2H), 7.42-7.43 (m, 2H), 7.53-7.55 (m,2H0, 8.15-8.17 (m, 2H), 8.71 (s, 1H), 8.90 (s, 1H), 9.46 (s, 1H)

2-{4-[3-(4-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.27 (m, 3H), 1.32-1.34 (m, 3H), 2.01(s, 3H), 3.75-3.76 (m, 4H), 3.81-3.82 (m, 4H), 3.88-3.93 (m, 2H),4.35-4.39 (m, 2H), 7.36-7.78 (m, 2H), 7.48-7.49 (m, 2H), 7.53-7.55 (m,2H), 8.15-8.16 (m, 2H), 8.66 (s, 1H), 8.91 (s, 1H), 9.83 (m, 1H)

5-Ethoxy-6-morpholin-4-yl-2′-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.19-1.22 (m, 3H), 1.26-1.29 (m, 3H),3.69-3.73 (m, 6H), 3.86-3.96 (m, 8H), 4.17 (s, 2H), 4.34-4.38 (m, 2H),7.33-7.34 (m, 2H), 7.66-7.68 (m, 2H), 9.34 (s, 2H), 10.50 (s, 1H), 11.58(s, 1H)

2′-[3-(4-Carbamoyl-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.29 (m, 3H), 1.32-1.35 (m, 3H),3.76-3.77 (m, 4H), 3.88-3.95 (m, 6H), 4.36-4.41 (m, 2H), 7.26 (s, 1H),7.73-7.75 (m, 2H), 7.86-7.90 (m, 3H), 9.38 (s, 2H), 10.62 (s, 1H), 11.81(s, 1H)2′-[3-(4-Acetylamino-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.24-1.29 (m, 3H), 1.32-1.35 (m, 3H), 2.05(s, 3H), 3.76-3.77 (m, 4H), 3.88-3.95 (m, 6H), 4.36-4.41 (m, 2H), 7.55(m, 4H), 9.35 (s, 2H), 9.89 (s, 1H), 10.46 (s, 1H), 11.45 (s, 1H)

5-Ethoxy-2-(4-{3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.27 (m, 3H), 1.32-1.34 (m, 3H), 2.92(s, 3H), 3.15-3.16 (m, 4H), 3.23-3.25 (m, 4H), 3.75-3.76 (m, 4H),3.81-3.82 (m, 4H), 3.88-3.93 (m, 2H), 4.35-4.39 (m, 2H), 6.92-6.94 (m,2H), 7.33-7.35 (m, 2H), 7.53-7.54 (m, 2H), 8.14-8.16 (m, 2H), 8.53 (s,1H), 8.86 (s, 1H)

5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.25-1.27 (m, 3H), 1.32-1.34 (m, 3H), 3.75(m, 4H), 3.83 (m, 4H), 3.90-3.91 (m, 2H), 4.35-4.39 (m, 2H), 6.98-6.99(m, 1H), 7.05-7.07 (m, 1H), 7.54-7.56 (m, 3H), 8.15-8.17 (m, 2H), 8.93(s, 1H), 9.09 (s, 1H)

2-{4-[3-(6-Acetylamino-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.20-1.23 (m, 3H), 1.27-1.30 (m, 3H), 2.02(s, 3H), 3.71-3.72 (m, 4H), 3.78 (m, 4H), 3.84-3.87 (m, 2H), 4.32-4.34(m, 2H), 7.50-7.52 (m, 2H), 7.77-7.79 (m, 1H), 7.96 (m, 1H), 8.11-8.13(m, 2H), 8.38 (s, 1H), 8.75 (s, 1H), 9.01 (s, 1H)

Example 2 Preparation of Compounds of Formula (I) in Scheme 5[2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl]-methanol

NaBH₄ (192 mg, 5 eq.) was added to a stirred solution of2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (378 mg, 1 eq.) in EtOH (12 ml) and the mixture reactedto reflux overnight.

The mixture was quenched with H₂O, the solvent removed in vacuo, and theresidue extracted with EA and washed with brine. The crude was purifiedby chromatography to give a product (267 mg, 80%).

¹H NMR (500 MHz, CDCl₃-d): δ1.33-1.36 (m, 3H), 3.80-3.90 (m, 10H), 4.30(s, 1H), 4.71 (s, 2H), 6.71-6.73 (m, 2H), 8.17-8.19 (m, 2H)

(2-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl)-methanol

NaBH₄ (0.64 g, 4 eq.) was added to a stirred solution of2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylic acid ethylester (1.34 g, 1 eq.) in EtOH (20 ml) and the mixture reacted to refluxfor 2 h. The mixture was quenched with H₂O, the solvent was removed invacuo, and the residue was extracted with EA, washed with brine, andconcentrated to give a product (1.13 g, 97.3%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.37 (m, 3H), 3.37 (s, 1H), 3.77-3.84(m, 10H), 4.63-4.64 (m, 2H)

(2-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carbaldehyde

To a suspension of Dess-Martin periodinane in CH₂Cl₂ (15%, 11.2 ml, 1.1eq) was added to a stirred solution of(2-chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl)-methanol (1.13 g, 1eq.) in CH₂Cl₂ (20 ml) and the mixture was reacted at r.t. for 2 h. Themixture was quenched with NaHCO₃ (sat), extracted with EA, and washedwith brine. The crude was purified by chromatography to give a product(1.08 g, 80.8%).

¹H NMR (500 MHz, CDCl₃-d₁) δ1.38-1.43 (m, 3H), 3.77-4.01 (m, 10H), 10.06(s, 1H)

4-[2-Chloro-5-ethoxy-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyrimidin-4-yl]-morpholine

A mixture of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylicacid ethyl ester (271.7 mg, 1 eq.), 1-methanesulfonyl-1-piperazine (197mg, 1.2 eq.) and trimethylorthoformate (0.33 ml, 3 eq.) was stirred in1,2-dichloroethane (6 ml) for 6 h at room temperature. To this was addedsodium triacetoxyborohydride (530 mg, 2.5 eq.) and the reaction mixturewas stirred overnight at room temperature. The mixture was then quenchedwith brine, exacted with CH₂Cl₂, and dried, and the solvent was removedin vacuo. The residue was triturated with EA/Hex to yield4-[2-chloro-5-ethoxy-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyrimidin-4-yl]-morpholineas a white solid (336 mg, 80%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.35-1.38 (m, 3H), 2.69-2.70 (m, 4H), 2.77(s, 3H), 3.26 (m, 4H), 3.59 (s, 2H), 3.79-3.86 (m, 10H)

3-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol

¹H NMR (500 MHz, DMSO-d₆): δ1.31-1.34 (m, 3H), 2.66 (m, 4H), 2.86 (s,3H), 3.10 (m, 4H), 3.61 (s, 2H), 3.74 (m, 8H), 3.90-3.93 (m, 2H),6.82-6.84 (m, 1H), 7.23-7.26 (m, 1H), 7.71 (m, 2H), 9.50 (s, 1H)

4-[2-Chloro-5-ethoxy-6-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yl]-morpholine

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.37 (m, 3H), 2.75 (s, 3H), 2.98 (m,4H), 3.18 (m, 4H), 3.65 (s, 2H), 3.79-3.82 (m, 10H)

4-[2-Chloro-5-ethoxy-6-(4-morpholin-1-ylmethyl)-pyrimidin-4-yl]-morpholine

A mixture of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylicacid ethyl ester (878 mg, 1 eq.), morpholine (0.34 ml, 1.2 eq.) andtrimethylorthoformate (1.06 ml, 3 eq.) was stirred in 1,2-dichloroethane(20 ml) for 6 hrs at room temperature. To this was added sodiumtriacetoxyborohydride (1.71 g, 2.5 eq.) and the reaction mixture wasstirred overnight at room temperature. The mixture was then quenchedwith brine, exacted with CH₂Cl₂, and dried, and the solvent was removedin vacuo. The crude was purified by chromatography to give a product(1.0 g, 91%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.36 (m, 3H), 2.56 (m, 4H), 3.50 (s,2H), 3.68-3.69 (m, 4H), 3.77 (s, 8H), 3.86-3.90 (m, 2H)

4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole

¹H NMR (500 MHz, CDCl₃-d₁): δ1.39-1.42 (m, 3H), 2.79 (s, 3H), 2.83-2.84(m, 4H), 3.30 (m, 4H), 3.81 (s, 2H), 3.86-3.88 (m, 8H), 3.95-3.99 (m,2H), 7.46-7.49 (m, 1H), 7.57-7.58 (m, 1H), 8.20-8.21 (m, 1H), 9.01 (s,1H)

4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.39 (m, 3H), 2.78 (s, 3H), 2.79-2.83(m, 4H), 3.28 (m, 4H), 3.71 (s, 2H), 3.78-3.83 (m, 8H), 3.89-3.92 (m,2H), 6.70-6.72 (m, 2H), 8.13-8.15 (m, 2H)

4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole

¹H NMR (500 MHz, CDCl₃-d₁): δ1.38-1.41 (m, 3H), 2.33 (s, 3H), 2.57 (m,4H), 2.79 (m, 4H), 3.77 (s, 2H), 3.85-3.88 (m, 8H), 3.97-4.01 (m, 2H),7.44-7.47 (m, 1H), 7.55-7.56 (m, 1H), 8.20-8.21 (m, 1H), 9.02 (s, 1H)

4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁) δ1.34-1.36 (m, 3H), 2.31 (s, 3H), 2.52 (m,4H), 2.73 (m, 4H), 3.66 (s, 2H), 3.77-3.83 (m, 8H), 3.89-3.93 (m, 2H),6.69-6.71 (m, 2H), 8.15-8.17 (m, 2H)

4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-1H-indazole

¹H NMR (500 MHz, CDCl₃-d₁): δ1.38-1.41 (m, 3H), 2.72 (m, 4H), 3.75-3.76(m, 6H), 3.85-3.88 (m, 8H), 3.99-4.03 (m, 2H), 7.46-7.47 (m, 1H),7.54-7.56 (m, 1H), 8.21-8.22 (m, 1H), 9.03 (s, 1H)

4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ1.34-1.39 (m, 3H), 2.68 (m, 4H), 3.64 (s,2H), 3.72-3.73 (m, 4H), 3.78-3.83 (m, 8H), 3.91-3.95 (m, 2H), 6.69-6.70(m, 2H), 8.15-8.16 (m, 2H)

1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ1.35-1.38 (m, 3H), 2.73 (s, 3H), 2.77 (m,4H), 3.24 (m, 4H), 3.71 (s, 2H), 3.81-3.82 (m, 8H), 3.87-3.92 (m, 2H),7.05 (m, 1H), 7.32-7.45 (m, 6H), 8.21-8.22 (m, 2H)

1-{4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.30-1.33 (m, 3H), 2.16 (s, 3H), 2.36-2.63(m, 8H), 3.53 (s, 2H), 3.74 (m, 8H), 3.91-3.93 (m, 2H), 6.98-6.99 (m,1H), 7.27-7.30 (m, 2H), 7.46-7.47 (m, 2H), 7.53-7.53 (m, 2H), 8.18-8.20(m, 2H), 8.83 (s, 1H), 9.00 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ1.35-1.38 (m, 3H), 2.65 (s, 4H), 3.66 (s,2H), 3.69-3.71 (m, 4H), 3.80-3.82 (m, 8H), 3.90-3.95 (m, 2H), 7.02-7.05(m, 1H), 7.23-7.37 (m, 6H), 8.21-8.23 (m, 2H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-ureahydrochloride

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.36 (m, 3H), 3.48-3.96 (m, 18H), 4.58(s, 2H), 6.97-6.99 (m, 1H), 7.27-7.30 (m, 2H), 7.46-7.48 (m, 2H),7.58-7.60 (m, 2H), 8.29-8.31 (m, 2H), 9.40 (s, 1H), 9.64 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-piperidin-1-ylmethyl-pyrimidin-2-yl)-phenyl]-3-Dphenyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ1.33-1.40 (m, 5H), 1.56-1.58 (m, 4H), 2.60(m, 4H), 3.64 (s, 2H), 3.77-3.80 (m, 8H), 3.86-3.90 (m, 2H), 6.93-6.96(m, 1H), 7.16-7.19 (m, 2H), 7.26-7.28 (m, 2H), 7.31-7.33 (m, 2H), 7.92(s, 1H), 8.03 (s, 1H), 8.14-8.16 (m, 2H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-piperidin-1-ylmethyl-pyrimidin-2-yl)-phenyl]-3-Phenyl-ureahydrochloride

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.36 (m, 3H), 1.86 (m, 4H), 2.08 (m,2H), 3.14 (m, 2H), 3.58 (m, 2H), 3.76-3.81 (m, 8H), 3.88-3.91 (m, 2H),4.48 (s, 2H), 6.95-6.98 (m, 1H), 7.26-7.29 (m, 2H), 7.46-7.47 (m, 2H),7.58-7.60 (m, 2H), 8.29-8.31 (m, 2H), 9.51 (s, 1H), 9.77 (s, 1H)

Example 3 Preparation of Compounds of Formula (I) in Scheme 15-Methoxy-pyrimidine-2,4-diol

A mixture of methyl methoxylacetate (15 ml, 1.0 eq) and ethyl formate(12.18 ml, 1.0 eq) was added dropwise to slurry of sodium methoxide(8.17 g, 1.0 eq) in toluene (100 ml) at ice both. After dropping at roomtemperature and stirring overnight, the resulting solution was dried invacuo. Then a mixture of residue, urea (9.09 g, 1.0 eq) and NaOMe (4.10g, 0.5 eq) in EtOH (100 ml) was refluxed at 110° C. for 4 hrs. After thesolvent was dried in vacuo, water and cone. HCl solution (5<pH<4) wereadded. After formation of white precipitate, the mixture was filteredand dried solid in vacuo. A product was obtained as a white solid (5.14g, 23.88%)

¹H NMR (500 MHz, DMSO-d₆): δ7.01 (s, 1H), 3.54 (s, 3H)

2,4-Dichloro-5-methoxy-pyrimidine

In ice bath, dimethyl-phenyl-amine (6.58 ml, 51.65 mmol, 0.5 eq) wasadded dropwise to a slurry of 5-methoxy-pyrimidine-2,4-diol (14.68 g,1.0 eq) in POCl₃ (47.42 ml, 5.0 eq) and refluxed overnight. Excess POCl₃was evaporated in vacuo and the residue was poured into ice-water. Afterformation of pink precipitates, the mixture was filtered and dried solidin vacuo. A product was obtained as a white solid (3.89 g, 20.83%)

¹H NMR (500 MHz, CDCl₃-d₁): δ8.18 (s, 1H), 4.01 (s, 3H)

4-(2-Chloro-5-methoxy-pyrimidin-4-yl)-morpholine

2,4-Dichloro-5-methoxy-pyrimidin (3.2 g, 1.0 eq) was stirred in toluene(20 ml) and a solution of morpholine (2.34 ml, 1.5 eq) in toluene (20ml) was added dropwise at −10˜0° C. After stirring the resultingsolution overnight at r.t., NH4Cl(aq) was added and the solution wasextracted with EA. The combined organic layers were washed with brine,dried and evaporated in vacuo. A product was obtained as a white solid(3.80 g, 93.08%)

¹H NMR (500 MHz, CDCl₃-d₁): δ7.71 (s, 1H), 3.84 (s, 3H), 3.82 (t, 4H),3.76 (t, 4H)

4-[5-Methoxy-2-(3-nitro-phenyl)-pyrimidin-4-yl]-morpholine

A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (0.2 g,1.0 eq), 3-nitrophenyl boronic acid (0.17 g, 1.2 eq), (PPh₃)₄Pd (0.10 g,0.1 eq) and 2 M Na₂CO₃ (1.3 ml, 3.0 eq) was heated at 80° C. andrefluxed overnight. The solvent was removed in vacuo, and the residuewas extracted with EA and water. The combined organic layers were washedwith brine, dried and evaporated in vacuo. The crude was purified bychromatography to give a yellow solid (0.11 g, 39.97%).

¹H NMR (500 MHz, CDCl₃-d₁): δ9.13 (s, 1H), 8.65 (d, 1H), 8.24 (d, 1H),8.03 (s, 1H), 7.60 (t, 1H), 3.93 (s, 3H), 3.88 (d, 4H), 3.85 (d, 4H)

4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.12 (d, 2H), 7.98 (s, 1H), 6.70 (d, 2H),3.86 (s, 3H), 3.82 (s, 8H)

4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol

¹H NMR (500 MHz, CDCl₃-d₁): δ8.20 (d, 2H), 7.96 (s, 1H), 6.91 (d, 2H),3.89 (s, 3H), 3.84 (m, 4H), 3.83 (m, 4H)

Phenyl-carbamic acid4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl ester

Phenyl isocyanate (0.03 ml, 2.0 eq) was added to a solution of4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol (0.05 g, 1.0 eq) indioxane (6 ml) and heated at 80° C. for 20 hrs. The solvent was removedin vacuo, and the residue was extracted with EA and water. The combinedorganic layers were washed with brine, dried and evaporated in vacuo.The crude was purified by chromatography to give a white solid (0.07 g,24.03%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.34 (d, 2H), 8.02 (s, 1H), 7.45 (d, 2H),7.33 (t, 2H), 7.27 (s, 1H), 7.12 (m, 1H), 6.90 (s, 1H), 3.90 (s, 3H),3.86 (m, 4H), 3.84 (m, 4H), 3.70 (s, 1H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.19 (d, 2H), 7.95 (s, 1H), 7.37 (d, 2H),7.33 (d, 2H), 7.27 (m, 2H), 7.23 (s, 1H), 7.19 (s, 1H), 7.05 (m, 1H),3.86 (s, 3H), 3.83 (m, 4H), 3.83 (m, 4H)

1-Ethyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.24 (d, 2H), 8.00 (s, 1H), 7.34 (d, 2H),6.35 (s, 1H), 4.72 (s, 1H), 3.89 (s, 3H), 3.83 (s, 4H), 3.30 (m, 2H),1.15 (m, 3H)

1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.25 (d, 2H), 7.99 (s, 1H), 7.39 (d, 2H),7.32 (m, 2H), 7.03 (m, 2H), 6.69 (s, 1H), 6.67 (s, 1H), 3.89 (s, 3H),3.84 (s, 8H)

1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.27 (d, 2H), 8.00 (s, 1H), 7.39 (d, 2H),7.30 (m, 1H), 7.24 (m, 1H), 7.00 (m, 1H), 6.80 (s, 1H), 6.78 (m, 1H),6.60 (s, 1H), 3.89 (s, 3H), 3.84 (s, 8H)

1-(3,4-Difluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.27 (d, 2H), 8.00 (s, 1H), 7.42 (m, 1H),7.39 (d, 2H), 7.00 (m, 1H), 6.97 (m, 1H), 6.75 (s, 1H), 6.68 (s, 1H),3.89 (s, 3H), 3.84 (s, 8H)

1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.35 (d, 2H), 8.01 (s, 1H), 7.82 (m, 1H),7.70 (m, 1H), 7.40 (d, 2H), 7.37 (d, 2H), 7.0 (d, 2H), 3.91 (s, 3H),3.84 (s, 8H)

1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.36 (d, 2H), 8.02 (s, 1H), 7.41 (d, 2H),7.33 (m, 2H), 7.26 (s, 1H), 7.11 (m, 1H), 6.94 (m, 1H), 3.91 (s, 3H),3.84 (s, 8H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.18 (s, 1H), 9.09 (s, 1H), 8.62 (d, 1H),8.17-8.19 (t, 3H), 8.13 (s, 1H), 7.95-7.97 (d, 1H), 7.54-7.56 (d, 2H),7.30-7.33 (m, 1H), 3.87 (s, 1H), 3.73-3.74 (m, 8H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.35 (s, 1H), 8.19-8.21 (d, 2H), 7.71-7.73(d, 3H), 6.42 (s, 1H), 4.22 (s, 4H), 3.94 (s, 3H), 3.87 (s, 4H), 2.84(s, 3H)

1-(3,4-Dimethoxy-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.18 (s, 1H), 8.89 (s, 1H), 8.13-8.17 (m,3H), 7.52-7.54 (d, 2H), 7.23 (s, 1H), 6.87-6.89 (m, 2H), 3.87 (s, 3H),3.70-3.74 (m, 14H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.10 (s, 1H), 9.01 (s, 1H), 8.18-8.19 (d,2H), 8.14 (s, 1H), 8.02 (s, 1H), 7.50-7.53 (m, 4H), 7.31-7.32 (d, 1H),3.87 (s, 3H), 3.73 (m, 8H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.11 (s, 1H), 8.98 (s, 1H), 8.17-8.18 (d,2H), 8.14 (s, 1H), 7.53-7.54 (d, 2H), 7.48-7.50 (d, 2H), 7.28-7.29 (d,2H), 4.18 (s, 2H), 3.96 (s, 2H), 3.87 (s, 3H), 3.69-3.74 (m, 10H)

1-(3-Fluoro-4-morpholin-4-yl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.11 (s, 1H), 8.98 (s, 1H), 8.16-8.17 (d,2H), 8.13 (s, 1H), 7.51-7.53 (d, 2H), 7.47-7.44 (s, 1H), 7.08-7.09 (m,1H), 6.95-6.99 (m, 1H), 3.87 (s, 3H), 3.73-3.74 (m, 12H), 2.92-2.94 (m,4H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.91 (s, 1H), 8.10-8.12 (d, 3H), 7.45-7.46(d, 2H), 6.25 (s, 1H), 3.86 (s, 3H), 3.72 (s, 8H), 3.58-3.60 (m, 4H),3.19-3.22 (m, 2H), 2.36-2.39 (m, 6H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methyl-piperazin-1-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.60 (s, 1H), 8.12-8.14 (d, 2H), 8.12 (s,1H), 7.77 (s, 1H), 7.60-7.62 (d, 2H), 3.86 (s, 3H), 3.73 (s, 8H),2.58-2.74 (m, 8H), 2.19 (s, 3H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.85 (s, 1H), 8.56 (s, 1H), 8.15-8.17 (d,2H), 8.13 (s, 1H), 7.50-7.52 (d, 2H), 7.31-7.33 (d, 2H), 6.88-6.90 (d,2H), 3.87 (s, 3H), 3.72-3.74 (m, 12H), 3.01-3.03 (m, 4H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.89 (s, 1H), 8.59 (s, 1H), 8.15-8.17 (d,2H), 8.13 (s, 1H), 7.50-7.52 (d, 2H), 7.31-7.32 (d, 2H), 6.87-6.89 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 3.38-3.39 (m, 4H), 2.67-2.69 (m,4H).

[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acidphenyl ester

A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(1.50 g, 1.0 eq.) and sodium bicarbonate solution (6 ml) in ethylacetate (6 ml) stirring 5 min. After dropping phenyl chloroformate (0.98ml, 1.2 eq) for 4 hrs at room temperature. The resultant mixtureextracted with EA and the combined organic layers were washed with brineand dried in vacuo to give a light brown solid (1.80 g, 40.5%) as theproduct.

¹H NMR (500 MHz, CDCl₃-d₁): δ8.36-8.38 (d, 2H), 7.95 (s, 1H), 7.61-7.63(d, 2H), 7.39-7.42 (m, 3H), 7.26 (s, 1H), 7.19-7.25 (m, 2H), 4.02 (s,4H), 3.90 (s, 3H), 3.85-3.86 (m, 4H)

4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.40-9.60 (m, 2H), 8.17-8.19 (d, 2H), 8.14(s, 1H), 7.80-7.82 (d, 3H), 7.53-7.56 (m, 4H), 7.18 (s, 1H), 3.87 (s,3H), 3.73-3.74 (m, 8H).

4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.30 (s, 1H), 9.15 (s, 1H), 8.18-8.20 (d,2H), 8.14 (s, 1H), 7.72-7.74 (d, 2H), 7.62-7.64 (d, 2H), 7.54-7.56 (d,2H), 7.21 (s, 2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H)

2-Nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.59 (s, 1H), 7.71-7.73 (d, 1H), 6.76-6.78(d, 1H), 6.20-6.30 (m, 2H), 1.33 (s, 12H).

4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine

A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (1.0 g, 1eq.),2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1.26 g, 1.1 eq.), dioxane (20 ml), Pd(PPh₃)₄ (0.05 g, 0.1 eq.) and 2Msodium carbonate (6.53 ml, 3.0 eq.) was heated to reflux overnight. Thesolvent was removed in vacuo, the residue extracted with EA, and theorganic layer washed with brine and dried. The crude was purified bychromatography to give a brown solid (2.08 g, 47.83%).

¹H NMR (500 MHz, CDCl₃-d₁): δ9.06 (s, 1H), 8.32-8.34 (d, 1H), 7.98 (s,1H), 6.84-6.86 (d, 1H), 6.20 (s, 2H), 3.86 (s, 3H), 3.84 (s, 8H)

1-(2-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea

A mixture of di-imidazol-1-yl-methanethione (0.5 g, 1.50 eq.), imidazole(0.03 g, 0.3 eq.) and CH₃CN (7 ml) was added dropwise to4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (0.5 g, 1.0eq.) in CH₂Cl₂ (5 ml) at 0° C. When S.M. is disappear in TLC, droppingbenzene-1,2-diamine (0.37 g, 3.0 eq) to the solution for 3 hrs at 50° C.The solvent was removed in vacuo. The resulting solution wascrystallized in a EA solution, and filtered to given a light yellowsolid, which was then dried in vacuo to give of a product (0.53 g,70.18%).

¹H NMR (500 MHz, DMSO-d₆): δ9.80 (s, 1H), 9.20 (s, 1H), 8.18-8.19 (d,2H), 8.15 (s, 1H), 7.63-7.64 (d, 2H), 7.09-7.10 (m, 1H), 6.95-6.96 (m,1H), 6.74-6.75 (m, 1H), 6.55-6.58 (m, 1H), 4.92 (s, 2H), 3.88 (s, 3H),3.72-3.75 (m, 8H).

4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine

A mixture of4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine (0.69g, 1.0 eq.) and Pd/C (Cat.) in MeOH/EA (10 ml/10 ml) was prepared. Themixture was sharked and H₂ gas was injected to the mixture for 4-6 hrsat room temperature. The mixture was filtered with Celite 454 and driedin vacuo to give a black sold (0.65 g, 99.9%) as a product.

¹H NMR (500 MHz, CDCl₃-d₁): δ8.03 (s, 1H), 7.49 (s, 1H), 7.36-7.38 (m,1H), 6.50-6.51 (d, 1H), 4.77 (s, 2H), 4.49 (s, 2H), 3.82 (s, 3H), 3.70(s, 8H).

(1H-Benzoimidazol-2-yl)-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine

A mixture of1-(2-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea(0.3 g, 1.0 eq.) and DCC (0.18 g, 1.3 eq.) in THF (10 ml) for 9 hrs at80-90° C. The mixture was dried in vacuo, crystallized in a EA solution,and then filtered to give a white solid (0.18 g, 68.36%), which was thendried in vacuo to give of a product.

¹H NMR (500 MHz, DMSO-d₆): δ11.2 (s, 1H), 9.87 (s, 1H), 8.20-8.22 (d,2H), 8.14 (s, 1H), 7.82-7.84 (d, 2H), 7.28-7.36 (d, 2H), 7.00 (s, 2H),3.87 (s, 3H), 3.74 (s, 8H).

5-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1H-benzoimidazol-2-ylamine

A mixture of4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine (0.58g, 1.0 eq.) and ACN/H2O (5 ml/1 ml). In ice bath, cyanogen bromide (0.3g, 1.5 eq) was added to mixture solution dropwisely. The solution wasstirred overnight at room temperature, quenched with a NaHCO₃ (sat.)solution, and then filtered to give a light brown solid (0.32 g,51.78%), which was dried in vacuo to give a product.

¹H NMR (500 MHz, DMSO-d₆): δ8.12 (s, 1H), 8.06 (s, 1H), 7.93-7.95 (d,1H), 7.14-7.5 (d, 1H), 6.63 (s, 2H), 3.86 (s, 3H), 3.74 (s, 8H).

1-(4-Dimethylaminomethoxy-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.86 (s, 1H), 8.60 (s, 1H), 8.15-8.17 (d,2H), 8.13 (s, 1H), 7.50-7.52 (d, 2H), 7.34-7.36 (d, 2H), 6.87-6.89 (d,2H), 4.00-4.02 (m, 2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 2.63-2.66 (m,2H), 1.90 (s, 6H)

3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ8.92 (s, 1H), 8.86 (s, 1H), 8.17-8.19 (d,2H), 8.14 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.53-7.55 (d, 2H),7.46-7.47 (d, 2H), 7.33-7.37 (m, 2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.15 (s, 1H), 8.20-8.22 (d, 2H), 8.14 (s,1H), 7.55-7.56 (d, 2H), 7.39 (s, 1H), 7.20 (s, 1H), 3.87 (s, 3H),3.73-3.74 (m, 8H)

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.22 (s, 1H), 8.18-8.20 (d, 2H), 8.14 (s,1H), 7.97 (s, 1H), 7.56-7.58 (d, 2H), 7.47 (s, 2H), 3.87 (s, 3H),3.73-3.74 (m, 8H), 3.17 (m, 4H), 3.06 (m, 4H), 1.16-1.19 (m, 3H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ10.00-10.20 (m, 2H), 8.19-8.21 (d, 2H), 8.16(s, 1H), 7.59-7.60 (d, 2H), 7.51 (s, 2H), 7.33-7.34 (d, 2H), 4.19 (s,2H), 3.96-3.98 (m, 2H), 3.88 (s, 3H), 3.72-3.75 (m, 8H).

[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.70 (s, 1H), 8.12 (s, 1H), 8.12-8.10 (d,2H), 7.45 (d, 2H), 5.90 (s, 2H), 3.86 (s, 3H), 3.72-3.73 (m, 8H).

[1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.95 (s, 1H), 8.75 (s, 1H), 8.15-8.17 (d,2H), 8.13 (s, 1H), 7.50-7.52 (d, 2H), 7.34-7.36 (d, 2H), 6.93-6.95 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.90 (s, 1H), 8.51 (s, 1H), 8.15-8.17 (d,2H), 8.13 (s, 1H), 7.70-7.72 (m, 1H), 7.50-7.52 (d, 2H), 6.84-6.86 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 3.30-3.44 (m, 8H), 2.54 (s, 3H).

1-Isopropyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.49 (s, 1H), 8.10-8.11 (m, 3H), 7.42-7.44(d, 2H), 6.05 (s, 1H), 3.86 (s, 3H), 3.72-3.76 (m, 8H), 1.09-1.10 (m,6H).

1-(4-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.89 (s, 1H), 8.40 (s, 1H), 8.13-8.15 (m,3H), 7.49-7.51 (d, 2H), 7.08-7.09 (d, 2H), 6.50-6.51 (d, 2H), 4.77 (s,2H), 3.86 (s, 3H), 3.73-3.74 (m, 8H).

4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid

¹H NMR (500 MHz, DMSO-d₆): δ9.38 (s, 1H), 9.27 (s, 1H), 8.18-8.20 (d,2H), 8.14 (s, 1H), 7.87-7.88 (d, 2H), 7.55-7.59 (m, 4H), 3.87 (s, 3H),3.73-3.74 (m, 8H)

1-(6-Bromo-pyridin-3-yl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.05-9.06 (d, 2H), 8.47 (s, 1H), 8.18-8.20(d, 2H), 8.14 (s, 1H), 7.90-7.92 (d, 1H), 7.52-7.56 (m, 3H), 3.87 (s,3H), 3.73-3.74 (m, 8H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.88 (s, 1H), 8.50 (s, 1H), 8.13-8.18 (m,4H), 7.72-7.74 (m, 2H), 7.50-7.52 (d, 2H), 6.81-6.83 (d, 1H), 3.87 (s,3H), 3.69-3.74 (m, 12H), 3.30-3.36 (m, 4H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.95-8.97 (d, 2H), 8.18-8.19 (d, 2H), 8.14(s, 1H), 7.52-7.54 (m, 4H), 7.36-7.37 (d, 2H), 3.87 (s, 3H), 3.73-3.74(m, 8H), 3.60 (s, 4H), 3.43-3.48 (m, 4H).

2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, DMSO-d₆): δ7.91-7.97 (m, 3H), 6.78-6.81 (m, 1H), 3.88(s, 3H), 3.80-3.84 (m, 8H).

[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.12 (s, 1H), 8.06-8.09 (m, 2H), 7.40-7.43(m, 3H), 7.27-7.29 (m, 2H), 7.21-7.22 (m, 2H), 3.90 (s, 3H), 3.84 (s,8H).

3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, DMSO-d₆): δ8.02 (s, 1H), 7.84-7.88 (m, 1H), 6.47-6.49(m, 1H), 6.40-6.43 (m, 1H), 3.88-3.89 (m, 5H), 3.81-3.88 (m, 8H).

[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ7.99-8.04 (m, 2H), 7.39-7.46 (m, 3H),7.15-7.27 (m, 5H), 3.90 (s, 3H), 3.82 (s, 8H).

4-{3-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.56 (s, 1H), 8.99 (s, 1H), 8.22-8.25 (m,1H), 8.15 (s, 1H), 7.99-8.05 (m, 2H), 7.82-7.84 (m, 3H), 7.52-7.54 (d,2H), 7.20 (s, 1H), 3.88 (s, 3H), 3.72-3.75 (m, 8H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.65 (s, 1H), 9.52 (s, 1H), 8.29 (s, 1H),8.20-8.21 (d, 2H), 8.14 (s, 1H), 7.74-7.76 (m, 1H), 7.59-7.61 (d, 2H),7.53-7.54 (m, 1H), 7.01-7.03 (m, 1H), 3.87 (s, 3H), 3.73-3.74 (m, 8H).

1-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.50 (s, 1H), 9.01 (s, 1H), 8.21-8.25 (m,1H), 8.15 (s, 1H), 7.98-8.05 (m, 2H), 7.49-7.51 (d, 2H), 7.29-7.31 (d,2H), 4.18 (s, 2H), 3.95-3.97 (m, 2H), 3.88 (s, 3H), 3.69-3.76 (m, 10H).

1-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.31 (s, 1H), 9.10 (s, 1H), 8.14 (s, 1H),7.89-7.92 (m, 1H), 7.47-7.54 (m, 3H), 7.26-7.28 (d, 2H), 7.18 (s, 1H),4.16 (s, 2H), 3.93-3.95 (m, 2H), 3.86 (s, 3H), 3.68-3.70 (m, 10H)

4-{3-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ8.16 (s, 1H), 7.92 (s, 1H), 7.80-7.82 (m,3H), 7.56-7.58 (m, 3H), 7.19-7.30 (m, 2H), 3.88 (s, 3H), 3.71-3.72 (m,8H), 3.16 (s, 2H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ10.30-10.10 (m, 2H), 8.60 (s, 1H), 8.31-8.32(d, 1H), 8.20-8.22 (m, 2H), 8.16 (s, 1H), 7.94 (s, 1H), 7.58-7.61 (m,2H), 7.36-7.37 (d, 1H), 3.88 (s, 3H), 3.72-3.76 (m, 8H).

N-(3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ9.92 (s, 1H), 8.92 (s, 1H), 8.75-8.78 (d,1H), 8.18-8.20 (m, 2H), 8.17 (s, 1H), 7.77 (s, 1H), 7.51-7.55 (m, 2H),7.18-7.19 (m, 2H), 3.87 (s, 3H), 3.73-3.75 (m, 8H), 1.90 (s, 3H).

N-(3-Dimethylamino-propyl)-4-{3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.08-9.10 (d, 2H), 8.36 (s, 1H), 8.18-8.19(d, 2H), 8.14 (s, 1H), 7.77-7.78 (d, 2H), 7.52-7.55 (m, 4H), 3.87 (s,3H), 3.73-3.74 (m, 8H), 2.26-2.29 (s, 2H), 2.15 (s, 6H), 1.63-1.66 (s,2H).

5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ9.14 (s, 2H), 7.96 (s, 1H), 5.20 (s, 2H),3.89 (s, 3H), 3.82 (s, 8H).

(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-carbamic acidphenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ9.47 (s, 2H), 8.51 (s, 1H), 7.99 (s, 1H),7.39-7.42 (m, 2H), 7.26-7.29 (m, 3H), 3.91 (s, 3H), 3.80 (s, 8H).

4-{3-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.39 (s, 2H), 8.19 (s, 1H), 7.86-7.88 (m,2H), 7.72-7.74 (m, 2H), 7.56-7.57 (m, 1H), 7.25 (s, 1H), 6.50-6.51 (d,1H), 5.58 (s, 1H), 3.90 (s, 3H), 3.82 (s, 4H), 3.73 (s, 4H).

N-(4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.09 (s, 1H), 8.91 (s, 1H), 8.16-8.17 (d,2H), 8.13 (s, 1H), 7.52-7.53 (d, 2H), 7.42-7.44 (d, 2H), 7.13-7.14 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 2.91 (s, 3H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.99 (s, 1H), 8.92 (s, 1H), 8.16-8.18 (d,2H), 8.13 (s, 1H), 7.52-7.53 (d, 2H), 7.47 (s, 1H), 7.15-7.16 (d, 1H),6.90-6.92 (d, 1H), 3.87 (s, 3H), 3.73-3.74 (m, 8H).

1-(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ11.59 (s, 1H), 10.47 (s, 1H), 9.37 (s, 2H),8.18 (s, 1H), 7.67-7.59 (d, 2H), 7.35-7.37 (d, 2H), 4.19 (s, 2H),3.96-3.98 (m, 2H), 3.90 (s, 3H), 3.81-3.82 (m, 2H), 3.72 (s, 8H).

2-Chloro-4-morpholin-4-yl-pyrimidin-5-ol

A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (5.0 g,1.0 eq.) and CH₂Cl₂ (20 ml) was added dropwise to a slurry of aluminumchloride (23.22 g, 8.0 eq.) in CH₂Cl₂ (30 ml) in ice bath. Afterdropping, the resulting solution was stirred overnight at roomtemperature. The resultant mixture was extracted with EA and thecombined organic layers were washed with brine and dried in vacuo togive a light yellow solid (4.18 g, 89.23%) as a product.

¹H NMR (500 MHz, DMSO-d₆): δ10.34 (s, 1H), 7.67 (s, 1H), 3.72-3.73 (m,4H), 3.65-3.66 (m, 4H).

4-(2-Chloro-5-(2-Morpholin-4ethoxy)-pyrimidin-4-yl)-morpholine

A mixture of 2-chloro-4-morpholin-4-yl-pyrimidin-5-ol (0.1 g, 1.0 eq.),4-(2-chloro-ethyl)-morpholine hydrochloric acid (0.12 g, 1.5 eq.) andK₂CO₃ (0.19 g, 3.0 eq.) in 1,4-dioxane (5 ml) was heated at 90° C. andrefluxed overnight. The resultant mixture was extracted with EA and thecombined organic layers were washed with brine and dried in vacuo togive a yellow solid (0.18 g, 68.02%) as a product.

¹H NMR (500 MHz, CDCl₃-d₁): δ7.73 (s, 1H), 4.07-4.09 (m, 2H), 3.86-3.88(m, 4H), 3.76-3.78 (m, 4H), 3.69-3.71 (m, 4H), 2.75-2.77 (m, 2H),2.50-2.53 (m, 4H).

4-(5-(2-morpholin-4-yl-ethoxy)-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.13-8.15 (d, 2H), 7.97 (s, 1H), 6.71-6.72(d, 2H), 4.12-4.14 (m, 2H), 3.90-3.91 (m, 4H), 3.87-3.88 (m, 4H),3.82-3.83 (m, 4H), 2.78-2.80 (m, 2H), 2.50-2.58 (m, 4H).

{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.31-8.32 (d, 2H), 8.01 (s, 1H), 7.53-7.55(d, 2H), 7.39-7.42 (m, 2H), 7.20-7.26 (m, 3H), 7.09 (s, 1H), 4.22-4.24(m, 2H), 3.91-3.93 (m, 4H), 3.83-3.85 (m, 4H), 3.77-3.80 (m, 4H),2.87-2.89 (m, 2H), 2.64-2.66 (m, 4H).

1-[4-(Morpholine-4-carbonyl)-phenyl]-3-{4-[4-morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.19-9.21 (d, 2H), 8.17-8.18 (d, 2H), 8.14(s, 1H), 7.53-7.55 (d, 4H), 7.35-7.37 (d, 2H), 4.17-4.19 (m, 2H),3.79-3.81 (d, 4H), 3.73 (s, 4H), 3.59 (s, 4H), 3.56 (s, 4H), 3.49 (s,4H), 2.70-2.71 (d, 2H), 2.36 (s, 4H).

1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.20 (s, 1H), 9.19 (s, 1H), 8.14-8.18 (m,3H), 7.53-7.54 (d, 2H), 7.48-7.50 (d, 2H), 7.27-7.29 (d, 2H), 4.18 (s,4H), 3.95-3.97 (m, 2H), 3.79-3.80 (s, 4H), 3.73 (s, 4H), 3.68-3.70 (m,2H), 3.55-3.56 (m, 4H), 2.69-2.71 (m, 2H), 2.45 (s, 4H).

4-(3-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-ureido)-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.30-9.50 (m, 2H), 8.14-8.18 (m, 3H),7.80-7.82 (m, 3H), 7.53-7.56 (m, 4H), 7.18 (s, 1H), 4.17-4.19 (m, 2H),3.79-3.80 (m, 4H), 3.73-3.74 (m, 4H), 3.55-3.56 (m, 4H), 2.69-2.71 (m,2H), 2.36 (s, 4H).

1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.68 (s, 1H), 9.45 (s, 1H), 8.34-8.35 (d,2H), 8.17-8.19 (d, 2H), 8.15 (s, 1H), 7.54-7.56 (d, 2H), 7.45-7.48 (d,2H), 4.18 (s, 2H), 3.79-3.80 (m, 4H), 3.73-3.74 (m, 4H), 3.55-3.57 (m,4H), 2.63-2.64 (m, 2H), 2.50-2.57 (m, 4H).

1-(4-Methanesulfonyl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.72 (s, 1H), 9.45 (s, 1H), 8.18-8.20 (d,2H), 8.14 (s, 1H), 7.81-7.82 (d, 2H), 7.71-7.73 (d, 2H), 7.56-7.58 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 3.15 (s, 3H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.52 (s, 1H), 9.23 (s, 1H), 8.19-8.20 (d,2H), 8.14 (s, 1H), 7.72-7.74 (d, 2H), 7.64-7.66 (d, 2H), 7.55-7.57 (d,2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 3.62-3.64 (m, 4H), 2.84 (m, 4H).

Pyridin-4-yl-carbamic acid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.50-8.51 (m, 2H), 7.88 (s, 1H), 7.39-7.45(m, 4H), 7.27-7.28 (m, 1H), 7.17-7.22 (m, 2H).

1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.32 (s, 1H), 9.22 (s, 1H), 8.35-8.36 (d,2H), 8.18-8.20 (d, 2H), 8.14 (s, 1H), 7.54-7.55 (d, 2H), 7.44-7.45 (d,2H), 3.87 (s, 3H), 3.70-3.74 (m, 8H).

1-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.85 (s, 1H), 8.57 (s, 1H), 8.13-8.17 (m,3H), 7.50-7.52 (d, 2H), 7.33-7.34 (d, 2H), 6.92-6.94 (d, 2H), 3.87 (s,3H), 3.72-3.73 (m, 8H), 3.22-3.24 (m, 4H), 3.15-3.16 (m, 4H), 2.92 (s,3H).

N-(5-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ10.37 (s, 1H), 9.01 (s, 1H), 8.82 (s, 1H),8.42 (d, 1H), 8.14-8.18 (d, 3H), 8.00-8.05 (m, 1H), 7.82-7.83 (m, 1H),7.52-7.54 (d, 2H), 3.87 (s, 3H), 3.73-3.74 (m, 8H), 2.06 (s, 3H).

5-Ethoxy-pyrimidine-2,4-diol

A mixture of ethyl ethoxylacetate (20 g, 1.0 eq) and ethyl formate(11.21 ml, 1.0 eq) was added dropwise to a slurry of sodium ethoxide(10.3 g, 1.0 eq) in toluene (100 ml) in ice both. After dropping at roomtemperature and stirring overnight, the resulting solution was dried invacuo. Then a mixture of residue, urea (9.09 g, 1.0 eq) and sodiumethoxide (10.3 g, 1.0 eq) in EtOH (100 ml) was refluxed at 110° C. for 6hrs. After the solvent was dried in vacuo, water and conc. HCl solution(5<pH<4) were added. After formation of white precipitates, the mixturewas filtered and dried solid in vacuo. A product was obtained as a whitesolid (7.76 g, 32%)

¹H NMR (500 MHz, DMSO-d₆): δ1.20-1.23 (m, 3H), 3.75-3.80 (m, 2H), 5.50(s, 2H), 7.05 (s, 1H)

2,4-Dichloro-5-ethoxy-pyrimidine

In ice bath, dimethyl-phenyl-amine (5.21 ml, 1.0 eq) was added dropwiseto slurry of 5-ethoxy-pyrimidine-2,4-diol (6.45 g, 1.0 eq) in POCl₃ (20ml, 5.0 eq) and refluxed overnight. Excess POCl₃ was evaporated in vacuoand the residue was poured into ice-water. After formation ofprecipitates, the mixture was filtered and dried solid in vacuo. Aproduct was obtained as a white solid (2.84 g, 35.57%)

¹H NMR (500 MHz, CDCl₃-d₁): δ1.47-1.50 (m, 3H), 4.16-4.20 (m, 2H), 8.13(s, 1H)

4-(2-Chloro-5-ethoxy-pyrimidin-4-yl)-morpholine

2,4-dichloro-5-ethoxy-pyrimidin (2.83 g, 1.0 eq) was stirred in toluene(20 ml) and a solution of morpholine (1.93 ml, 1.5 eq) in toluene (20ml) was added dropwise at −10˜0° C. After stirring the resultingsolution overnight at r.t., NH₄Cl(aq) was added to the solution and thesolution was extracted with EA. The combined organic layers were washedwith brine, dried and evaporated in vacuo. A product was obtained as awhite solid (2.7 g, 73.5%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.41-1.44 (m, 3H), 3.75-3.77 (m, 4H),3.83-3.85 (m, 4H), 4.01-4.05 (m, 2H), 7.69 (s, 1H)

4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ1.41-1.44 (m, 3H), 3.83 (m, 8H), 4.05-4.09(m, 2H), 6.70-6.72 (m, 2H), 7.97 (s, 1H), 8.11-8.12 (m, 2H)

[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acidphenyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.72-3.78 (m, 8H),4.09-4.13 (m, 2H), 7.24-7.29 (m, 3H), 7.42-7.46 (m, 2H), 7.58-7.60 (m,2H), 8.12 (s, 1H), 8.21-8.23 (m, 2H), 10.40 (s, 1H)

4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.73-3.78 (m, 8H),4.10-4.14 (m, 2H), 7.18 (m, 1H), 7.51-7.55 (m, 4H), 7.81-7.83 (m, 3H),8.12 (s, 1H), 8.18-8.20 (m, 2H), 8.94 (s, 1H), 8.97 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 2.65-2.67 (m, 4H),3.36-3.37 (m, 4H), 3.71-3.76 (m, 8H), 4.08-4.12 (m, 2H), 6.85-6.87 (m,2H), 7.30-7.31 (m, 2H), 7.49-7.51 (m, 2H), 8.10-8.14 (m, 3H), 8.57 (s,1H), 8.85 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.68-3.70 (m, 2H),3.72-3.73 (m, 4H), 3.76-3.78 (m, 4H), 3.95-3.96 (m, 2H), 3.97-4.14 (m,2H), 4.19 (s, 2H), 7.28-7.30 (m, 2H), 7.47-7.53 (m, 4H), 8.12 (s, 1H),8.17-8.19 (m, 2H), 8.79 (s, 1H), 8.87 (s, 1H)

4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.73-3.78 (m, 8H),4.10-4.14 (m, 2H), 7.18 (m, 2H), 7.49-7.50 (m, 4H), 7.57-7.59 (m, 2H),8.08 (s, 1H), 8.14-8.16 (m, 2H), 8.93 (s, 1H), 9.06 (s, 1H)

N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 2.01 (s, 3H), 3.72-3.77(m, 8H), 4.09-4.14 (m, 2H), 7.36-7.38 (m, 2H), 7.47-7.52 (m, 4H), 8.12(s, 1H), 8.16-8.18 (m, 2H), 8.64 (s, 1H), 8.83 (s, 1H), 9.82 (s, 1H)

N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 2.92 (s, 3H), 3.72-3.77(m, 8H), 4.09-4.14 (m, 2H), 7.36-7.38 (m, 2H), 7.14-7.16 (m, 2H),7.41-7.43 (m, 2H), 7.50-7.52 (m, 2H), 8.12 (s, 1H), 8.16-8.18 (m, 2H),8.70 (s, 1H), 8.82 (s, 1H), 9.45 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.72-3.77 (m, 8H),4.09-4.14 (m, 2H), 6.92 (m, 1H), 7.16-7.17 (m, 1H), 7.49-7.53 (m, 2H),8.12 (s, 1H), 8.17-8.18 (m, 2H), 8.83 (s, 1H), 8.89 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 2.92 (s, 1H), 3.15-3.16(m, 4H_, 3.23-3.24 (m, 4H), 3.72-3.73 (m, 4H), 3.76-3.77 (m, 4H),4.09-4.13 (m, 4H), 6.92-6.94 (m, 2H), 7.33-7.35 (m, 2H), 7.50-7.52 (m,2H), 8.11 (s, 1H), 8.15-8.17 (m, 2H), 8.57 (s, 1H), 8.84 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.42-3.43 (m, 4H), 3.49(m, 4H), 3.72-3.73 (m, 4H), 3.76-3.77 (m, 4H), 4.09-4.13 (m, 2H),7.35-7.37 (m, 2H), 7.51-7.54 (m, 4H), 8.12 (s, 1H), 8.17-8.19 (m, 2H),8.92-8.96 (m, 2H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.73-3.74 (m, 4H),3.76-3.77 (m, 4H), 4.10-4.14 (m, 2H), 6.99-7.01 (m, 1H), 7.06-7.08 (m,1H), 7.51-7.53 (m, 2H), 7.58 (m, 1H), 8.12 (s, 1H), 8.16-8.18 (m, 2H),8.73 (s, 1H), 8.73 (s, 1H), 11.46 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.16 (s, 3H), 3.73-3.74(m, 4H), 3.77-3.78 (m, 4H), 4.10-4.14 (m, 2H), 7.54-7.56 (m, 2H),7.69-7.71 (m, 2H), 7.82-7.84 (m, 2H), 8.12 (s, 1H), 8.19-8.20 (m, 2H),9.03 (s, 1H), 9.25 (s, 1H)

5-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1,3-dihydro-benzoimidazol-2-one

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 3.16 (s, 3H), 3.73-3.74(m, 4H), 3.77-3.78 (m, 4H), 4.10-4.14 (m, 2H), 6.95-6.97 (m, 1H), 7.83(m, 1H), 7.93-7.94 (m, 1H), 8.11 (s, 1H)

N-(5-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ1.34-1.37 (m, 3H), 2.09 (s, 3H), 3.73-3.74(m, 4H), 3.77-3.78 (m, 4H), 4.10-4.14 (m, 2H), 7.52-7.54 (m, 2H),7.81-7.83 (m, 1H), 8.00-8.02 (m, 1H), 8.12 (s, 1H), 8.17-8.18 (m, 2H),8.42-8.43 (m, 1H), 8.75 (s, 1H), 8.94 (s, 1H), 10.38 (s, 1H)

N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ1.35-1.37 (m, 3H), 2.99 (s, 3H), 3.73-3.74(m, 4H), 3.77-3.78 (m, 4H), 4.13-4.14 (m, 2H), 7.26-7.28 (m, 1H),7.38-7.41 (m, 1H), 7.97-7.99 (m, 1H), 8.16-8.18 (m, 2H), 9.83 (s, 1H)

N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-2,4-difluoro-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.37 (m, 3H), 3.71-3.75 (m, 8H),4.09-4.13 (m, 2H), 7.14-7.15 (m, 1H), 7.22-7.26 (m, 1H), 7.29-7.32 (m,1H), 7.49-7.53 (m, 1H), 7.88-7.92 (m, 2H), 8.04 (s, 1H), 8.12 (s, 1H),10.74 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.37 (m, 3H), 3.71-3.72 (m, 4H),3.76-3.77 (m, 4H), 4.08-4.12 (m, 2H), 7.44-7.45 (m, 2H), 7.52-7.54 (m,2H), 8.11 (s, 1H), 8.18-8.19 (m, 2H), 8.35 (m, 1H), 9.04 (s, 1H), 9.15(s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-ureahydrochloride

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.37 (m, 3H), 3.71-3.72 (m, 4H),3.76-3.77 (m, 4H), 4.08-4.12 (m, 2H), 7.44-7.45 (m, 2H), 7.52-7.54 (m,2H), 8.11 (s, 1H), 8.18-8.19 (m, 2H), 8.35 (m, 1H), 9.04 (s, 1H), 9.15(s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.33-1.37 (m, 3H), 2.84 (m, 4H), 3.63 (m,4H), 3.73-3.74 (m, 4H), 3.77-3.78 (m, 4H), 4.10-4.14 (m, 2H), 7.54 (m,2H), 7.64-7.66 (m, 2H), 7.71-7.73 (m, 2H), 8.13 (s, 1H), 8.19-8.20 (m,2H), 9.05 (s, 1H), 9.29 (s, 1H)

Example 4 Preparation of Compounds of Formula (I) in Scheme 22,4,6-Trichloro-5-methylsulfanyl-pyrimidine

Barbituric acid (5.2 g, 40.6 mmol.), 3.5 ml of DMSO, 20 ml of aceticacid, and 6.0 ml of aceticanhydride were heated progressively to 90-100°C. This temperature was maintained for 4 hr and then 130 ml of waterwere added to the mixture. After cooling and filtering, the precipitatewas washed with acetone. The dimethylsulfonium-substituted barbituricacid weighed 6.1 g (80.1%).

¹H NMR (500 MHz, DMSO-d6): δ10.14 (s, 2H), 2.96 (s, 6H)

The above product (5.2 g, 27.5 mmol.) was reacted with 30 ml ofphosphorus oxychloride and 5.0 ml of dimethylaniline. After heating for24 hr under reflux, the reaction mixture was subjected to hydrolysis iniced salt water. The reaction mixture was subjected to filtration andthe resulting solid was washed with water. After drying in vacuo, aproduct of 4.5 g (60.1%) was obtained.

¹H NMR (500 MHz, CDCl₃-d₁): δ2.80 (s, 3H)

4-(2,6-Dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine

A mixture of 2,4,6-trichloro-5-methylsulfanyl-pyrimidine (4.0 g, 17.4mmol.), morpholine (2.3 g, 26.1 mmol, 1.5 eq.) and THF (20 ml) wasstirred at room temperature for 2.0 hr. The reaction mixture was driedand the solvent was evaporated. Thereafter, a 0.1 N HCl washing freemorpholine was added to the solution. The solution was extracted with EAand the EA in the solution was removed by evaporation. A crude productwas obtained. Purification of the crude by flash chromatography onsilica gel (Hexane/EtOAc 6:1) gave a gray solid of 2.34 g (48.2%).

¹H NMR (500 MHz, CDCl₃-d₁): δ3.89 (t, 4H), 3.80 (t, 4H), 2.32 (s, 3H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine(200 mg, 0.71 mmol.),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (172.0 mg,0.781 mmol.), (PPh₃)₄Pd (437 mg, 0.07 mmol.), 2M Na₂CO₃ (1.0 ml, 2.13mmol, 3.0 eq.) and dioxane (15.0 ml) was added to the reaction vesselwhich was flushed with argon. The reaction mixture was stirred at 90° C.for 12 hrs and then dried so that the solvent was evaporated. Thereaction mixture was partitioned between EA and water. The organiclayers were collected, washed with brine, dried over MgSO₄, filtered andevaporated in vacuo. The resulting residue was purified by flashchromatography on silica gel (Hexane/EtOAc 3:2) to give a pale yellowsolid of 102 mg (42.3%).

¹H NMR (500 MHz, DMSO-d₆): δ8.19 (d, 2H), 6.72 (d, 2H), 3.85 (s, 8H),2.35 (s, 3H).

4-[6-Chloro-2-(3-methoxy-phenyl)-5-methylsulfanyl-pyrimidin-4-yl]-morpholine

¹H NMR (500 MHz, CDCl₃-d₁): δ7.96 (d, 1H), 7.90 (d, 1H), 7.36 (t, 1H),7.01 (d, 1H), 3.87 (m, 11H), 2.36 (s, 3H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol

¹H NMR (500 MHz, CDCl₃-d₁): δ8.27 (d, 2H), 6.88 (d, 2H), 5.08 (s, 1H),3.86 (s, 8H), 2.35 (s, 3H)

3-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol

¹H NMR (500 MHz, CDCl₃-d₁): δ7.93 (d, 1H), 7.82 (dd, 1H), 7.32 (t, 1H),6.96 (m, 1H), 5.31 (b, 1H), 3.87 (q, 8H), 2.36 (s, 3H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-benzenesulfonamide

¹H NMR (500 MHz, Acetone-d₆): δ8.52 (d, 2H), 7.99 (d, 2H), 6.71 (s, 2H),3.83 (t, 8H), 2.41 (s, 3H)

5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-ylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ9.05 (d, 1H), 8.36 (dd, 1H), 6.53 (s, 1H),4.87 (b, 2H), 3.85 (t, 8H), 2.35 (s, 3H)

5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indole

¹H NMR (500 MHz, CDCl₃-d₁): δ8.72 (d, 1H), 8.28-8.24 (dd, 2H), 7.43-7.41(d, 1H), 7.25 (dd, 1H), 7.25-7.24 (d, 1H), 3.89 (m, 8H), 2.37 (s, 3H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indazole

¹H NMR (500 MHz, CDCl₃-d₁): δ8.98 (s, 1H), 8.30 (d, 1H), 7.64 (d, 1H),7.49 (s, 1H), 3.91 (s, 8H), 2.41 (s, 1H)

N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide

A mixture of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(30 mg, 0.091 mmol.), methanesulfonyl chloride (15.5 mg, 0.136 mmol, 1.5eq.) and CH₂Cl₂ was added to the reaction vessel and flushed with argon.The reaction mixture was stirred at r.t. for 2 hrs. The reaction mixturewas partitioned between CH₂Cl₂ and NaHCO_(3 (aq)), the organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated in vacuo. Awhite solid of 30.3 mg (82.1%) was obtained as the product.

¹H NMR (500 MHz, CDCl₃-d₁): δ8.34 (d, 2H), 7.26 (d, 1H), 6.72 (s, 1H),3.87 (d, 8H), 3.06 (s, 3H), 2.35 (t, 3H)

N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-acetamide

¹H NMR (500 MHz, CDCl₃-d₁): δ10.25 (s, 1H), 8.21 (d, 2H), 7.72 (d, 2H),3.84 (t, 4H), 3.84 (t, 4H), 3.75 (t, 4H), 2.33 (s, 3H), 2.08 (s, 3H)

N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-benzenesulfonamide

¹H NMR (500 MHz, CDCl₃-d₁): δ8.24 (d, 2H), 7.80 (t, 2H), 7.53 (t, 1H),7.44 (t, 2H), 7.14 (d, 2H), 6.75 (s, 1H), 3.84 (d, 8H), 2.34 (d, 3H)

Methanesulfonicacid-4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.42 (m, 2H), 7.36 (q, 2H), 3.86 (m, 8H),3.17 (s, 3H), 2.37 (s, 3H)

Benzenesulfonicacid-4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.29-8.27 (d, 2H), 7.84-7.83 (d, 2H),7.68-7.65 (d, 1H), 7.53-7.50 (d, 2H), 7.05-7.04 (s, 1H), 3.86 (t, 8H),3.18 (s, 3H), 2.36 (s, 3H)

Methanesulfonicacid-3-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.33 (d, 1H), 8.23 (d, 1H), 7.49 (d, 1H),7.42 (d, 1H), 3.86 (t, 8H), 3.18 (s, 3H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea

A mixture of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(40 mg, 0.118 mmol.), 2-chloro-4-isocyanato-1-trifluoro methyl-benzene(39 mg, 0.178 mmol.), CH₂Cl₂ (1.0 ml), and toluene (2.0 ml) was added toa reaction vessel which was flushed with argon. The reaction mixture wasstirred at 90° C. for 16 hrs. After cooling and filtering, theprecipitate was washed with a minor portion of CH₂Cl₂ again to give awhite solid of 26.7 mg (40.3%).

¹H NMR (500 MHz, Acetone-d₆): δ8.66 (s, 1H), 8.59 (s, 1H), 8.30 (dd,2H), 8.16 (d, 1H), 7.77 (dd, 1H), 7.66 (dd, 2H), 7.56 (d, 1H), 3.90 (t,4H), 3.82 (t, 4H), 2.39 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-chloro-pyridin-4-yl)-urea

¹H NMR (500 MHz, Acetone-d₆): δ8.72 (s, 1H), 8.61 (s, 1H), 8.50 (d, 2H),8.32 (s, 1H), 7.67 (d, 2H), 7.38 (d, 1H), 3.91 (t, 4H), 3.82 (t, 4H),2.39 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.27 (d, 2H), 7.43 (d, 2H), 7.34 (t, 4H),7.12 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 3.96 (d, 8H), 2.35 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-dimethylamino-phenyl)-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.31 (b, 1H), 8.29 (s, 1H), 7.89 (b, 1H),8.27 (s, 1H), 7.91 (s, 1H), 7.66 (d, 2H), 7.36 (d, 2H), 6.73 (d, 2H),3.90 (t, 4H), 3.82 (t, 4H), 2.80 (d, 6H), 2.39 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-fluoro-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.04 (s, 1H), 8.82 (s, 1H) 8.21-8.19 (d,2H), 7.58 (d, 2H), 7.49-7.46 (dd, 2H), 7.15-7.11 (t, 2H), 3.84 (d, 4H),3.76 (d, 4H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-phenyl)-urea

¹H NMR (500 MHz, Acetone-d₆): δ8.56 (s, 1H), 8.52 (s, 1H), 8.31-8.30 (d,2H) 7.68-7.66 (d, 2H), 7.62-7.60 (d, 1H), 7.30-7.29 (d, 2H), 7.20 (s,1H), 3.71 (t, 4H), 3.82 (t, 4H), 2.39 (s, 3H).

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-difluoro-phenyl)-urea

¹H NMR (500 MHz, Acetone-d₆): δ8.77 (s, 1H), 8.73 (s, 2H), 8.30 (d, 2H),7.82 (m, 1H), 7.66 (d, 2H), 7.21 (m, 1H), 3.91 (t, 4H), 3.82 (t, 4H),2.39 (s, 3H)

[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

Trimethylsilyl isocyanate (136 mg, 5 eq.) was added to a stirredsolution of4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(80 mg, 0.237 mmol.) in THF (2.0 ml) and the mixture was reacted toreflux for 16 hrs. The reaction mixture was extracted with EA and washedwith brine. The crude was purified by Chromatography (Hexane/EtOAc 1:1)to give a product 28.1 mg (31.2%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.58 (s, 1H), 8.33 (s, 2H), 7.66 (s, 2H),6.42 (b, 2H), 3.92 (t, 4H), 3.82 (t, 4H), 2.39 (s, 3H)

1-(2-Chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.26 (d, 2H), 7.40 (d, 2H), 7.12 (s, 1H),5.58 (t, 1H), 3.86 (d, 8H), 3.62 (m, 4H), 2.35 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-ethyl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.26 (d, 2H), 7.39 (d, 2H), 6.97 (s, 1H),5.05 (b, 1H), 3.85 (d, 8H), 3.29 (d, 2H), 2.35 (s, 3H), 1.15 (t, 3H)

1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.4 (s, 1H), 9.76 (s, 1H), 9.14 (s, 1H),8.50 (dd, 1H), 7.66 (d, 1H), 7.55 (d, 2H), 7.32 (t, 2H), 7.04 (s, 1H),3.87 (t, 4H), 3.76 (t, 4H), 2.36 (d, 3H)

1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ12.1 (s, 1H), 9.25 (s, 1H), 8.57 (dd, 1H),8.44 (s, 1H), 7.59 (d, 1H), 7.28 (dd, 2H), 6.90 (s, 1H), 6.80 (s, 1H),3.88 (t, 8H), 2.38 (s, 3H)

1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-ethyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.52 (s, 1H), 9.04 (s, 1H), 8.41 (dd, 1H),8.00 (b, 1H), 7.51 (d, 1H), 3.85 (t, 4H), 3.75 (t, 4H), 3.20 (t, 2H),2.34 (s, 3H), 1.10 (t, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-imidazolidin-2-one

A mixture of1-(2-chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(20 mg, 0.045 mmol.), 10% NaOH (0.5 ml), THF (2.0 ml), and H₂O (1.0 ml)was added to a vessel. The reaction mixture was stirred at 80° C. for 8hr and then dried, and the solvent was evaporated. The reaction mixturewas partitioned between EA and 0.1N HCl, the organic layer was washedwith brine, dried over MgSO₄, filtered and evaporated in vacuo. Theresulting residue was purified by flash chromatography on silica gel(Hexane/EtOAc 3:1) to give a gray solid of 11.4 mg (62.3%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.33 (d, 2H), 7.64 (d, 2H), 4.88 (s, 1H),4.01 (m, 2H), 3.87 (t, 8H), 3.66 (m, 2H), 2.36 (s, 3H)

(2-Chloro-ethyl)-carbamic acid4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester

A mixture of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol(80.0 mg, 0.236 mmol), 1-chloro-2-isocyanato-ethane (43.1 mg, 0.354mmol, eq=1.5.), toluene and CH₂Cl₂ was added to the reaction vessel andflushed with argon. The reaction mixture was stirred at 80° C. for 16hrs and then dried, and the solvent was evaporated. The reaction mixturewas partitioned between EA and water, the organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated in vacuo. The resultingresidue was purified by flash chromatography on silica gel (Hexane/EtOAc2:1) to give a gray solid of 58.9 mg (58.1%)

¹H NMR (500 MHz, CDCl₃-d₁): δ8.36 (d, 2H), 7.23 (d, 2H), 5.50 (s, 1H),3.87 (d, 8H), 3.70 (t, 2H), 3.64 (dd, 2H), 2.36 (s, 3H)

[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

A mixture of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(915 mg, 2.717 mmol.) in EA (20 ml) and NaHCO₃ (20 ml) the reaction wasstirred at r.t. then added dropwise to slurry of phenyl chloroformate(851 mg, 0.543 mmol, 2.0 eq) at reaction for 2 hr. The reaction mixturewas partitioned between EA/NaHCO₃, the organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated in vacuo. The residuewas recrystallized by (Hexane/EtOAc) to give a pale yellow product of1056 mg (85.1%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.35-8.33 (d, 2H), 7.54-7.52 (d, 2H),7.41-7.38 (dd, 2H), 7.26-7.18 (m, 4H), 3.87 (s, 8H), 2.36 (s, 3H)

[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.18 (b, 1H), 8.14-8.11 (m, 2H), 7.43-7.40(dd, 2H), 7.35 (s, 1H), 7.28-7.26 (s, 1H), 7.22-7.20 (s, 2H), 3.88-3.87(s, 4H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.28 (d, 2H), 7.40 (d, 2H), 6.82 (b, 1H),5.91 (b, 1H), 3.85 (d, 8H), 2.86 (d, 3H), 2.35 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-morpholin-4-yl-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.32-8.31 (d, 2H), 8.23 (s, 1H), 7.59-7.57(d, 2H), 5.87 (s, 1H), 4.01 (b, 2H), 3.87-3.87 (d, 8H), 3.72 (b, 2H),3.09 (b, 2H), 2.77 (b, 2H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.31 (s, 1H), 9.10 (s, 1H), 8.63 (d, 1H),8.20 (t, 3H), 7.95 (dd, 1H), 7.55 (d, 2H), 7.32 (s, 1H), 3.84 (d, 4H),3.77 (d, 4H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.27-9.25 (d, 2H), 8.38-8.36 (d, 2H),8.23-8.22 (d, 2H), 7.61-7.59 (d, 2H), 7.46-7.45 (d, 2H), 3.85-3.84 (d,4H), 3.77-3.75 (d, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea

¹H NMR (500 MHz, CDCl₃-d₁): δ8.25 (d, 2H), 7.89 (b, 1H), 7.44 (d, 2H),5.88 (b, 1H), 3.85 (d, 8H), 3.65 (t, 4H), 3.55 (dd, 2H), 2.51 (d, 2H),2.47 (s, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(2-dimethylamino-ethoxy)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.63 (s, 1H), 9.31 (s, 1H), 8.19-8.18 (d,2H), 7.59-7.57 (d, 2H), 7.44-7.42 (d, 2H), 6.97-6.95 (d, 2H), 4.45 (s,2H), 3.90 (s, 2H), 3.84-3.38 (dd, 8H), 3.24 (s, 6H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ11.01 (b, 1H), 9.72 (b, 1H), 8.23 (d, 2H),7.65 (d, 2H), 7.35 (s, 1H), 7.11 (s, 1H), 3.84 (d, 4H), 3.77 (d, 4H),2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.32-8.30 (d, 2H), 8.25 (d, 1H), 7.58-7.56(d, 2H), 5.54 (b, 1H), 3.87-3.85 (d, 8H), 3.09 (b, 2H), 2.89 (b, 2H),2.65 (b, 2H), 2.35 (s, 3H), 2.34 (b, 2H) 2.17 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-4-morpholin-4-yl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.16 (s, 1H), 8.93 (s, 1H), 8.20-8.19 (d,2H), 7.59-7.57 (d, 2H), 7.47-7.44 (d, 1H), 7.10-7.08 (d, 1H), 7.00 (d,1H), 3.84-3.83 (d, 4H), 3.76-3.72 (dd, 8H), 2.94-2.93 (d, 4H), 2.34 (s,3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid ethyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.17 (t, 2H), 8.09 (s, 1H), 8.01 (s, 1H),7.90 (d, 2H), 7.43 (t, 4H), 4.33 (dd, 2H), 3.86 (s, 4H), 3.83 (s, 4H),2.34 (s, 3H), 1.36 (dd, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.18 (s, 1H), 8.98 (d, 1H), 8.21-8.19 (d,2H), 7.61-7.59 (d, 2H), 7.51-7.49 (d, 2H), 7.30-7.28 (d, 2H), 4.18 (s,2H), 3.97-3.95 (dd, 2H), 3.84-3.76 (d, 4H), 3.76-3.75 (d, 4H), 3.70-3.68(dd, 2H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.19-9.18 (d, 2H), 8.23-8.21 (d, 2H), 8.03(s, 1H) 7.62-7.58 (t, 3H), 7.54-7.53 (d, 1H), 7.34-7.33 (d, 1H),3.84-3.83 (d, 4H), 3.77-3.75 (d, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.02 (s, 1H), 8.60 (s, 1H), 8.19-8.18 (d,2H), 7.58-7.56 (d, 2H), 7.31-7.30 (d, 2H), 6.89-6.87 (d, 2H), 3.84-3.83(d, 4H), 3.76-3.75 (d, 4H), 3.05 (s, 4H), 2.45-2.44 (d, 4H), 2.36-2.34(d, 3H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.03 (s, 1H), 8.61 (s, 1H), 8.20-8.18 (d,2H), 7.58-7.56 (d, 2H), 7.33-7.31 (d, 2H), 6.89-6.87 (d, 2H), 3.84-3.83(d, 4H), 3.76-3.75 (d, 4H), 3.40-3.38 (s, 4H), 2.69-2.67 (d, 4H), 2.32(s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.96 (s, 1H), 8.54 (s, 1H), 8.16-8.14 (d,2H), 7.54-7.52 (d, 2H), 7.29-7.28 (d, 2H), 6.86-6.84 (d, 2H), 3.80-3.79(d, 4H), 3.72-3.69 (d, 8H), 2.99-2.97 (d, 4H), 2.32 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.12 (s, 1H), 8.60 (s, 1H), 8.20-8.18 (d,2H), 8.16 (d, 1H), 7.70-7.60 (d, 1H), 7.58-7.56 (d, 2H), 6.82-6.81 (d,1H), 3.84-3.83 (d, 4H), 3.76-3.75 (d, 4H), 3.43-3.39 (d, 4H), 2.40-2.39(d, 4H), 2.38-2.36 (d, 3H), 2.30 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.21 (s, 1H), 8.72 (s, 1H), 8.20-8.18 (d,3H), 7.74-7.72 (d, 1H), 7.59-7.57 (d, 2H), 6.84-6.82 (d, 1H), 3.84-3.83(d, 4H), 3.76-3.75 (d, 4H), 3.71-3.69 (d, 4H), 3.32-3.30 (d, 4H), 2.34(s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.73 (s, 1H), 9.53 (s, 1H), 8.30-8.29 (d,1H), 8.24-8.22 (d, 2H), 7.78-7.75 (dd, 1H), 7.67-7.65 (d, 2H), 7.56-7.55(d, 1H), 7.05-7.02 (d, 1H), 3.85-3.84 (d, 4H), 3.77-3.76 (d, 4H),2.36-2.34 (s, 3H)

2-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-thiophene-3-carboxylicacid methyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ9.72 (s, 1H), 8.32-8.30 (d, 2H), 8.06-8.05(d, 1H), 7.57-7.55 (dd, 2H), 7.48-7.46 (d, 1H), 3.91 (s, 4H), 3.90-3.88(d, 3H), 3.87-3.86 (d, 4H), 2.36 (s, 3H)

1-Benzo[1,3]dioxol-5-yl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.13 (s, 1H), 8.82 (s, 1H), 8.20-8.18 (d,2H), 7.58-7.56 (d, 2H), 7.21 (s, 1H), 6.84-6.78 (dd, 2H), 5.97 (s, 2H),3.84-3.83 (d, 4H), 3.76-3.76 (d, 4H), 2.36-2.34 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.13 (s, 1H), 9.04 (s, 1H), 8.23-8.21 (d,2H), 7.84-7.82 (d, 3H), 7.61-7.59 (d, 2H), 7.54-7.52 (d, 2H), 7.20 (b,1H), 3.85-3.84 (d, 4H) 3.77-3.76 (d, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-dimethoxy-phenyl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.94 (s, 1H), 8.60 (s, 1H), 8.21-8.19 (d,2H), 7.59-7.57 (d, 2H), 7.21 (s, 1H), 6.88-6.87 (s, 2H), 3.84 (s, 3H),3.75 (s, 8H), 3.71 (s, 3H), 2.36 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.82 (b, 1H), 9.26 (s, 1H), 8.22-8.20 (d,2H), 7.95 (s, 1H), 7.64-7.63 (d, 2H), 7.46-7.44 (t, 2H), 3.84-3.77 (d,4H), 3.76-3.75 (d, 4H), 3.10-3.09 (t, 4H), 2.52-2.49 (d, 4H), 2.46-2.45(s, 3H), 2.34-2.21 (s, 3H)

N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ9.33 (b, 1H), 9.29 (b, 1H), 8.58 (s, 1H),8.23-8.21 (d, 2H), 7.86-7.85 (d, 1H), 7.79-7.76 (d, 1H), 7.63-7.58 (m,3H), 3.84-3.76 (d, 4H), 3.75-3.75 (d, 4H), 2.36-2.34 (s, 3H)

N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ9.93 (s, 1H), 9.05 (s, 1H), 8.91 (s, 1H),8.21-8.19 (d, 2H), 7.78 (s, 1H), 7.59-7.58 (d, 2H), 7.21-7.17 (dd, 3H),3.84-3.83 (d, 4H), 3.77-3.76 (d, 4H), 2.36-2.34 (s, 3H), 2.03-1.98 (s,3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.21 (s, 1H), 9.13 (s, 1H), 8.22-8.21 (d,2H), 7.60-7.59 (d, 2H), 7.54-7.53 (d, 2H), 7.37-7.36 (d, 2H), 3.84 (d,4H), 3.76 (d, 4H), 3.39-3.35 (d, 4H), 2.50-2.46 (d, 4H), 2.36-2.34 (s,3H), 2.03-1.98 (s, 3H)

1-(6-Bromo-pyridin-3-yl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.71 (b, 2H), 8.51-8.50 (d, 1H), 8.22-8.20(d, 2H), 7.93-7.91 (dd, 1H), 7.62-7.60 (d, 2H), 7.56-7.54 (d, 1H),3.84-3.76 (d, 4H), 3.76 (s, 4H), 2.36-2.34 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid

¹H NMR (500 MHz, DMSO-d₆): δ9.39-9.38 (d, 1H), 9.33-9.32 (d, 1H),8.22-8.20 (d, 2H) 7.90-7.88 (dd, 2H), 7.61-7.59 (dd, 4H), 3.84-3.81 (d,4H), 3.76-3.74 (d, 4H), 2.33 (s, 3H)

1-(2-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea

A mixture of bis-(2,5-dihydro-imidazol-1-yl)-methanethione (29.2 mg,0.164 mmol), imidazole (3.7 mg, 0.05 mmol, 0.5 eq) in CH₃CN (5 ml) wasstirred at 0° C., then added dropwise to a slurry of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(50 mg, 0.109 mmol.). The resulting mixture was reacted 3.0 hrs at r.t.and then benzene-1,2-diamine (23.6 mg, 0.218 mmol, 2.0 eq) was addedthereinto. The reaction resulted in a white solid, which was filtered,collected and evaporated in vacuo to give 49.5 mg of a white compound(68.5%).

¹H NMR (500 MHz, DMSO-d₆): δ10.01 (b, 1H), 9.65 (b, 1H), 8.22-8.20 (d,2H), 7.75-7.74 (d, 2H), 7.10-7.09 (d, 1H), 6.97-6.95 (d, 1H), 6.75-6.74(d, 1H), 6.58-6.55 (d, 1H), 4.95 (b, 2H), 3.85-3.84 (d, 4H), 3.76-3.75(d, 4H), 2.36-2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ8.63-8.63 (d, 1H), 8.44-8.43 (d, 1H),8.26-8.24 (d, 2H), 7.98-7.97 (d, 1H), 7.70-7.66 (m, 4H), 7.12-7.04 (d,1H), 3.86-3.85 (d, 4H), 3.76-3.75 (d, 4H), 2.35 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ10.10 (b, 1H), 10.01 (b, 1H), 8.23-8.22 (d,2H), 7.70-7.68 (d, 2H), 7.53-7.50 (d, 2H), 7.36-7.34 (d, 2H), 4.20-3.98(d, 2H), 3.97-3.96 (d, 2H), 3.85-3.75 (dd, 4H), 3.74-3.71 (dd, 6H),2.36-2.34 (s, 3H)

(1H-Benzoimidazol-2-yl)-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine

A mixture of1-(2-amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea(120 mg, 1.0 eq.) and DCC (0.18 g, 0.271 mmol, 1.1 eq.) in THF (8 ml)was reacted for 9 hrs at 80-90° C. The resulting mixture was dried invacuo, crystallized in EA solution, filtered to give a yellow solid(69.5 mg, 62.3%), which was then dried in vacuo to give a product.

¹H NMR (500 MHz, DMSO-d₆): δ10.78 (b, 1H), 9.98 (s, 1H), 8.25-8.23 (d,2H), 7.90-7.89 (d, 2H), 7.24-7.20 (d, 2H), 7.02 (s, 2H), 3.85-3.84 (d,4H), 3.77-3.75 (d, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isopropyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.67 (s, 1H), 8.15-8.13 (d, 2H), 7.50-7.49(d, 2H), 6.02 (s, 1H), 3.84-3.83 (d, 4H), 3.76-3.75 (d, 4H), 2.33 (s,3H), 1.11-1.09 (s, 6)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.34-9.24 (d, 2H), 8.22-8.20 (d, 2H),7.61-7.60 (d, 2H), 7.55-7.53 (d, 2H), 7.37-7.36 (d, 2H), 3.84-3.83 (d,4H), 3.77-3.76 (d, 4H), 3.60-3.39 (m, 8H), 2.36-2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(5-morpholin-4-yl-pyridin-2-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.31 (b, 1H), 9.27 (s, 1H), 8.23-8.21 (d,2H), 7.97 (s, 1H), 7.65-7.63 (d, 2H), 7.47 (s, 2H), 3.85-3.83 (d, 4H),3.77-3.74 (dd, 8H), 3.09-3.07 (d, 4H), 2.49-2.34 (s, 3H)

1-(4-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.09 (s, 1H), 8.48 (s, 1H), 8.18-8.16 (d,2H), 7.57-7.55 (d, 2H), 7.10-7.08 (d, 2H), 6.52-6.50 (d, 2H), 4.79 (s,2H), 3.83-3.83 (d, 4H), 3.76-3.75 (d, 4H), 2.49-2.46 (s, 3H)

1-tert-Butyl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.60 (s, 1H), 8.14-8.13 (d, 2H), 7.48-7.46(d, 2H), 6.12 (s, 1H), 3.83-3.81 (d, 4H), 3.76-3.74 (d, 4H), 2.33 (s,3H), 1.29-1.26 (d, 9H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.11-8.06 (dd, 2H), 7.15-7.14 (m, 1H),3.87-3.86 (d, 8H), 2.36 (s, 3H)

4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.04-8.01 (dd, 1H), 6.74-6.72 (d, 1H),6.67-6.65 (d, 1H), 3.89 (s, 4H), 3.84-3.83 (s, 4H), 2.36 (s, 3H)

6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine

¹H NMR (500 MHz, DMSO-d₆): δ8.99 (s, 2H), 7.35 (s, 2H), 3.84-3.83 (d,4H), 3.74-3.73 (d, 4H), 2.32 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(1H-indazol-4-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ10.45 (s, 1H), 8.55 (s, 1H), 8.29-8.26 (d,2H), 7.98-7.95 (d, 2H), 7.67 (s, 1H), 7.43-7.41 (d, 1H), 7.26-7.23 (d,1H), 6.42-6.41 (d, 1H), 6.12 (s, 1H), 3.87-3.85 (d, 4H), 3.77-3.76 (d,4H), 2.50-2.50 (s, 3H)

N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.87 (b, 1H), 9.03 (s, 1H), 8.78 (s, 1H),8.21-8.19 (d, 2H), 7.59-7.57 (d, 2H), 7.44-7.42 (d, 2H), 7.16-7.14 (d,2H), 3.85-3.83 (d, 4H), 3.77-3.75 (d, 4H), 2.92 (s, 3H), 2.34 (s, 3H)

[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.64 (s, 1H), 8.34-8.31 (s, 1H), 8.01-7.96(dd, 2H), 6.34 (s, 2H), 3.84-3.83 (d, 4H), 3.76-3.75 (d, 4H), 2.34 (s,3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.31 (s, 1H), 892 (s, 1H), 8.37-8.34 (s,1H), 8.08-8.51 (d, 2H), 7.50-7.4 (d, 2H), 7.3-7.3 (d, 23H), 4.19 (s,2H), 3.97-3.95 (s, 2H), 3.85-3.85 (d, 4H), 3.77-3.75 (d, 4H), 3.71-3.69(s, 2H), 2.34 (s, 3H)\

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.34 (s, 1H), 9.03 (s, 1H), 8.05-8.01 (d,1H), 7.62-7.59 (d, 1H), 7.50-7.46 (d, 2H), 7.31-7.23 (m, 3H), 4.18 (s,2H), 3.97-3.95 (s, 2H), 3.83-3.82 (d, 4H), 3.75-3.74 (d, 4H), 3.71-3.69(d, 2H), 2.36-2.34 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.14 (s, 2H), 8.23-8.21 (s, 2H), 7.75-7.73(s, 2H), 7.63-7.62 (d, 2H), 7.61-7.59 (d, 2H), 7.22 (s, 2H), 3.85 (d,4H), 3.77-3.76 (d, 4H), 2.36 (s, 3H)

N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ9.83 (s, 1H), 9.03 (s, 1H), 8.72 (s, 1H),8.20-8.19 (d, 2H), 7.59-7.57 (d, 2H), 7.49-7.48 (d, 2H), 7.38-7.36 (d,2H), 3.84-3.83 (d, 4H), 3.77-3.76 (d, 4H), 2.36 (s, 3H), 2.01 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.16 (s, 1H), 8.95 (s, 1H), 8.21-8.19 (d,2H), 7.60-7.58 (d, 2H), 7.43 (s, 1H), 7.14-7.12 (s, 1H), 6.92-6.90 (m,1H), 3.85-3.83 (d, 4H), 3.77-3.76 (d, 4H), 2.36-2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.74 (s, 1H), 9.22 (s, 1H), 8.76-8.76 (d,1H), 8.23-8.21 (d, 2H), 7.63-7.59 (d, 2H), 6.87-6.87 (d, 1H), 3.84-3.83(d, 4H), 3.77-3.76 (s, 4H), 2.31 (s, 3H)

1-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ11.57 (s, 1H), 10.24 (b, 1H), 9.39 (d, 2H),7.70-7.68 (d, 2H), 7.37-7.35 (d, 2H), 4.19-4.18 (d, 2H), 3.98-3.90 (d,2H), 3.90 (s, 4H), 3.77-3.71 (m, 6H), 2.35 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.35 (s, 1H), 9.16 (s, 1H), 8.04-8.02 (d,1H), 7.84-7.82 (d, 3H), 7.62-7.52 (m, 3H), 7.26-7.24 (m, 2H), 3.84-3.82(d, 4H), 3.75-3.73 (d, 4H), 2.35 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.45 (s, 1H), 8.97 (s, 1H), 8.37-8.33 (d,1H), 8.09-8.01 (dd, 2H), 7.85-7.83 (d, 3H), 7.54-7.52 (d, 2H), 7.21 (s,1H), 3.86-3.85 (d, 4H), 3.77-3.75 (d, 4H), 2.34 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.62 (s, 1H), 9.01 (s, 1H), 8.33-8.32 (d,1H), 8.09-8.02 (dd, 2H), 7.76-7.75 (d, 2H), 7.64-7.63 (d, 1H), 7.23 (s,1H), 3.86-3.85 (d, 4H), 3.77-3.75 (d, 4H), 2.32 (s, 3H)

4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.37 (s, 1H), 9.28 (s, 1H), 8.05-8.02 (d,1H), 7.75-7.73 (d, 2H), 7.63-7.58 (m, 3H), 7.26-7.22 (m, 3H), 3.82-3.81(d, 4H), 3.73-3.72 (d, 4H), 2.31 (s, 3H)

N-(5-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide

¹H NMR (500 MHz, DMSO-d₆): δ10.38 (s, 1H), 9.20 (s, 1H), 8.90 (s, 1H),8.43-8.42 (d, 1H), 8.21-8.20 (d, 2H), 7.91-7.89 (d, 1H), 7.84-7.82 (dd,1H), 7.60-7.59 (d, 2H), 3.84-3.83 (d, 4H), 3.77-3.75 (d, 4H), 2.34 (s,3H), 2.08-2.06 (d, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.01 (s, 1H), 8.61 (s, 1H), 8.20-8.18 (d,2H), 7.58-7.56 (d, 2H), 7.35-7.33 (d, 2H), 6.94-6.93 (d, 2H), 3.85-3.83(d, 4H), 3.77-3.75 (d, 4H), 3.25-3.22 (d, 4H), 3.17-3.15 (d, 4H), 2.92(s, 3H), 2.34 (s, 3H)

4-[3-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-ureido]-benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ11.85 (s, 1H), 10.75 (s, 1H), 9.41 (s, 2H),7.87-7.85 (d, 2H), 7.80-7.78 (d, 2H), 7.27 (s, 2H), 3.91-3.90 (d, 4H),3.77-3.75 (d, 4H), 2.35 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea

¹H NMR (500 MHz, DMSO-d₆): δ11.49 (s, 1H), 9.07 (s, 1H), 8.87 (s, 1H),8.21-8.20 (d, 2H), 7.59-7.58 (d, 3H), 7.09-7.07 (d, 1H), 7.02-7.00 (d,1H), 3.84 (d, 4H), 3.76 (d, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.36 (s, 1H), 9.23 (s, 1H), 8.23-8.22 (d,2H), 7.74-7.72 (d, 2H), 7.67-7.65 (d, 2H), 7.62-7.61 (d, 2H), 3.84 (d,4H), 3.76 (d, 4H), 3.63 (s, 4H), 2.84 (s, 4H), 2.34 (s, 3H)

1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.24 (s, 1H), 9.14 (s, 1H), 8.22-8.20 (d,2H), 7.61-7.59 (d, 2H), 7.54-7.52 (d, 2H), 7.36-7.34 (d, 2H), 3.84-3.83(d, 4H), 3.77-3.75 (d, 4H), 2.72 (b, 4H), 2.38 (s, 6H), 2.36-2.34 (m,4H), 1.84 (b, 2H), 1.43-1.41 (b, 2H)

Example 5 Preparation of Compounds of Formula (I) in Scheme 35-(Methylthio)pyrimidine-2,4-diol

5-iodouracil (476 mg, 2 mmole) was placed in a dry and argon-flushedSchlenk-tube equipped with a magnetic stirring bar and a septum. Withvigorous stirring, the substrate was dried for 15 min in high vacuum toexclude the presence of water in the hygroscopic substrate. Then, asolution of LiCl in THF (0.5M; 8 ml; 4 mmole, 2.0 eq) was added andafter stirring for some minutes at r.t., the substrate dissolved to givea clear and colourless solution. The solution was cooled to −20° C. andMeMgCl (3M in THF; 1.33 ml, 4 mmole, 2 eq) was added dropwise. Aftercompletion of the addition, the resulting clear solution was stirred at−20° C. for 20 min. Afterward, i-PrMgCl (1.32 M in THF; 1.82 ml, 2.40mmole, 1.20 eq) was added slowly and the resulting mixture was allowedto warm up to room temperature. After one hour, a thick, grayish slurryhad formed and the mixture was cooled to −20° C. and S-methylmethanesulfonothioate (328 mg, 2.6 mmole, 1.3 eq) was obtained.Afterwards, the mixture was warmed up to r.t. and stirred at thattemperature until TLC indicated completion of the reaction. Afterquenching with MeOH, the mixture was transferred to a separation funnelcontaining water (40 ml). By careful addition of 2.0 M HCl, the pH ofthe mixture was adjusted to ca. 5-6. The aqueous layer was extractedwith EA, the combined organic layers were dried (Na₂SO₄) and evaporated.Recrystallization from MeOH afforded the product as a colorless,crystalline solid which was dried in high vacuum (64%).

¹H NMR (500 MHz, DMSO-d₆): δ7.41 (s, 1H), 2.49 (s, 3H)

2,4-Dichloro-5-(methylthio)pyrimidine

5-(methylthio)pyrimidine-2,4-diol (0.5 g, 3.16 mmole), POCl₃ (3 ml) anddimethylaniline (0.5 ml) were heated to reflux for 12 hrs. The mixturewas cooled to 0° C. and carefully poured over ice. The white solidformed was separated by filtration and dried under vacuum to afford theproduct 2,4-dichloro-5-(methylthio)pyrimidine (0.49 g, 80%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.29 (s, 1H), 2.55 (s, 3H)

4-(2-Chloro-5-(methylthio)pyrimidin-4-yl)morpholine

A solution of the 2,4-dichloro-5-(methylthio)pyrimidine (1.16 g, 6mmole) in acetone (10 ml) at 0° C. containing Na₂CO₃ (1.1 eq, 6.6 mmole,0.7 g) was treated dropwise with a solution of morpholine (1.0 eq, 6.6mmole, 0.6 ml) in acetone (2 ml) and stirred for 1 hr at 0° C. TLC(EA:Hex=1:2, Rf=0.6) showed completion of the reaction to give twoproducts. The acetone was removed in vacuo, the residue was partitionedbetween water and EA, and the organic layer was dried (MgSO₄) andevaporated in vacuo. Column chromatography (EA/Hex=1/6) gave the product(700 mg, 47%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.13 (s, 1H), 3.79-3.82 (m, 8H), 2.39 (s,3H)

4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)benzenamine

A mixture of 4-(2-chloro-5-(methylthio)pyrimidin-4-yl)morpholine (0.3 g,1.22 mmole), 4-aminophenylboronic acid pinacol ester (0.58 g, 2.68mmole), sodium bicarbonate (0.28 g, 2.68 mmole), Pd(PPh₃)₄ (0.14 g,0.122 mmole), dioxane (15 ml) and H₂O (3.5 ml) was heated to reflux.After 12 hrs, the reaction mixture was cooled, diluted with EA, washedwith brine, and dried (MgSO₄), and the solvent was removed in vacuo.Purification on silica gel (EA/Hex=1/2) yielded the desired compound(180 mg, 49%).

¹H NMR (500 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.01˜8.03 (d, 2H), 6.58˜6.60(d, 2H), 5.59 (s, 2H), 3.73˜3.74 (d, 4H), 3.64˜3.66 (d, 4H), 2.42 (s,3H)

3-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenol

¹H NMR (500 MHz, CDCl₃-d₁): δ8.37 (s, 1H), 7.92˜7.94 (d, 2H), 7.85 (s,1H), 7.30˜7.33 (m, 1H), 6.93˜6.95 (m, 1H), 3.85˜3.87 (m, 4H), 3.79˜3.80(m, 4H), 2.44 (s, 3H)

4-(2-(4-(Methylsulfonyl)phenyl)-5-(methylthio)pyrimidin-4-yl)morpholine

¹H NMR (500 MHz, DMSO-d₆): δ 8.46˜8.48 (m, 3H), 7.91˜7.93 (m, 2H), 7.42(br, 2H), 3.75˜3.77 (m, 4H), 3.68˜3.69 (m, 4H), 2.49 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-phenylurea

A mixture of 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)benzeneamine(0.1 g, 0.33 mmole), co-solvent (5 ml, DMF/THF=6/40) and phenylisocyanate (0.2 ml, 0.92 mmole) was heated to 80° C. After 12 hrs, thereaction mixture was cooled, and the THF removed in vacuo. Then themixture was diluted with EA, washed with brine, and dried (MgSO₄). Thesolvent was removed in vacuo. Purification of the residue on silica gel(EA/Hex=1/2) yielded the desired compound (42.2 mg, 30.4%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.82 (s, 1H), 8.41 (s, 1H),8.24˜8.26 (d, 2H) 7.56˜7.57 (d, 2H), 7.46˜7.47 (d, 2H), 7.27˜7.30 (m,2H), 6.98 (m, 1H), 3.74 (s, 4H), 3.68 (s, 4H), 2.47 (s, 3H)

1-Ethyl-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.39 (s, 1H), 8.17˜8.19 (d,2H), 7.47˜7.49 (d, 2H), 6.20˜6.22 (m, 2H), 3.73˜3.75 (m, 4H), 3.65˜3.67(m, 4H), 3.10˜3.12 (m, 2H), 2.36 (s, 3H), 1.04˜1.06 (m, 3H)

1-(3,4-Difluorophenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.05 (s, 1H), 9.01 (s, 1H), 8.41 (s, 1H),8.24˜8.26 (d, 2H), 7.67˜7.70 (m, 1H), 7.57˜7.66 (d, 2H), 7.34˜7.36 (m,1H), 7.13˜7.15 (br, 1H), 3.74 (s, 4H), 3.68 (s, 4H), 2.48 (s, 3H)

1-(4-Fluorophenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.41 (s, 3H), 8.21˜8.23 (d, 2H), 7.57˜7.59,(d, 2H), 7.48˜7.50 (m, 2H), 7.08˜7.12 (m, 2H), 3.75 (s, 4H), 3.67 (s,4H), 2.47 (s, 3H).

Phenyl 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenylcarbamate

The phenyl chloroformate (0.84 ml, 6.68 mmole, 2.5 eq) was added to amixture of 4-(5-(methylthio)-4morpholinopyrimidin-2-yl)benzeneamine(0.84 g, 2.18 mmole, 1 eq), NaHCO₃(aq) (1M, 6.3 ml, 6.3 mmole 2.2 eq)and ACN (13 ml) at 0□. The reaction mixture was stirred for 8 hrs andthen dried. The reaction mixture was partitioned between EA and water,the organic layer was washed with brine, dried over MgSO₄, filtered andevaporated in vacuo. The resulting residue was purified by flashchromatography on silica gel (Hexane/EtOAc 2:1) to give a yellow solid(80%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.38 (s, 1H), 8.35˜8.36 (d, 2H), 7.53˜7.55(d, 2H), 7.39˜7.42 (m, 2H), 7.1˜7.2 (m, 3H), 3.79˜3.87 (d, 8H), 2.44 (s,3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-morpholinourea

¹H NMR (500 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.41 (s, 1H), 8.20˜8.22 (d,2H), 7.91 (s, 1H), 7.67˜7.69 (d, 2H), 3.66˜3.76 (m, 13H), 2.49 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea

¹H NMR (500 MHz, CD₃OD-d₄): δ8.63 (s, 1H), 8.35 (s, 1H), 8.26˜8.28 (d,2H), 8.19˜8.20 (d, 1H), 8.03˜8.05 (d, 1H), 7.56˜7.57 (d, 2H), 7.37˜7.40(m, 1H), 3.85 (s, 8H), 2.46 (s, 3H)

1-(3-Fluoro-4-morpholinophenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.91 (s, 1H), 8.41 (s, 1H),8.23˜8.25 (d, 2H), 7.55˜7.56 (d, 2H), 7.43˜7.44 (d, 1H), 7.07 (d, 1H),6.98˜7.0 (t, 1H), 3.67˜3.76 (m, 12H), 2.93˜2.94 (s, 4H), 2.48 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(4-(3-oxomorpholino)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.09 (s, 1H), 8.96 (s, 1H), 8.42 (s, 1H),8.24˜8.26 (d, 2H), 7.56˜7.58 (d, 2H), 7.48˜7.50 (d, 2H), 7.28˜7.30 (d,2H), 4.18 (s, 2H), 3.95˜3.97 (t, 2H), 3.68˜3.76 (m, 8H), 2.48 (s, 3H)

1-(4-(4-Methylpiperazin-1-yl)phenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.94 (s, 1H), 8.58 (s, 1H), 8.41 (s, 1H),8.22˜8.24 (d, 2H), 7.54˜7.56 (d, 2H), 7.29˜7.31 (d, 2H), 6.86˜6.88 (d,2H), 3.74˜3.76 (d, 4H), 3.67˜3.68 (d, 4H), 3.03˜3.04 (s, 4H), 2.43˜2.44(s, 3H), 2.36 (s, 4H), 2.21 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(4-thiomorpholinophenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.65 (s, 1H), 8.41 (s, 1H),8.22˜8.23 (d, 2H), 7.55˜7.57 (d, 2H), 7.31˜7.33 (d, 2H), 6.86˜6.88 (d,2H), 3.75˜3.76 (d, 4H), 3.67˜3.38 (d, 4H), 3.37˜3.39 (d, 4H), 2.67˜2.68(d, 4H), 2.47 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(4-morpholinophenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.67 (s, 1H), 8.38 (s, 1H),8.22˜8.24 (d, 2H), 7.54˜7.56 (d, 2H), 7.28˜7.34 (d, 2H), 6.85˜6.89 (d,2H), 3.68˜3.76 (m, 8H), 3.67˜3.68 (d, 4H), 3.02˜3.03 (d, 4H), 2.49 (s,3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(thiazol-2-yl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (s, 1H), 8.27˜8.28 (d, 2H), 7.59˜7.67(d, 2H), 7.38 (s, 1H), 6.85˜6.89 (s, 1H), 3.76 (s, 4H), 3.68 (s, 4H),2.49 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.27 (s, 1H), 9.20 (s, 1H), 8.42 (s, 1H),8.25˜8.26 (d, 2H), 8.03 (s, 1H), 7.58˜7.59 (d, 3H), 7.50˜7.53 (t, 1H),7.31˜7.32 (d, 1H), 3.75 (s, 4H), 3.68 (s, 4H), 2.48 (s, 3H)

Ethyl4-(3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)ureido)benzoate

¹H NMR (500 MHz, DMSO-d₆): δ 9.29 (s, 1H), 9.18 (s, 1H), 8.42 (s, 1H),8.25˜8.27 (d, 2H), 7.88˜7.90 (d, 2H), 7.57˜7.61 (t, 4H), 4.25˜4.30 (q,2H), 3.75˜3.76 (d, 4H), 3.67˜3.69 (d, 4H), 2.48 (s, 3H), 1.25˜1.32 (t,3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(6-morpholinopyridin-3-yl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.67 (s, 1H), 8.41 (s, 1H),8.19˜8.22 (m, 3H), 7.77 (m, 1H), 7.55˜7.56 (d, 2H), 6.85˜6.89 (d, 1H),3.75˜3.76 (m, 4H), 3.67˜3.70 (m, 4H), 2.48 (s, 3H)

1-(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.01 (s, 1H), 8.67 (s, 1H), 8.41 (s, 1H),8.22˜8.24 (d, 2H), 8.17 (s, 1H), 7.7 (d, 2H), 7.54˜7.56 (d, 2H),6.85˜6.89 (d, 1H), 3.74˜3.76 (d, 4H), 3.67˜3.68 (d, 4H), 3.37˜3.38 (d,4H), 2.47 (s, 3H), 2.38˜2.40 (d, 4H), 2.20 (s, 3H)

4-(3-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)ureido)benzamide

¹H NMR (500 MHz, DMSO-d₆): δ 9.10 (s, 1H), 9.08 (s, 1H), 8.42 (s, 1H),8.25˜8.27 (d, 2H), 7.21˜7.83 (m, 3H), 7.57˜7.59 (d, 2H), 7.51˜7.53 (d,2H), 7.19 (s, 1H), 3.75˜3.76 (d, 4H), 3.67˜3.69 (d, 4H), 2.47 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.81 (s, 1H), 8.40 (s, 1H), 8.18˜8.20 (d,2H), 7.49˜7.50 (d, 2H), 5.96 (d, 2H), 3.74 (s, 4H), 3.67 (s, 4H), 2.46(s, 3H)

1-(2-Aminophenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)thiourea

To a stirred solution of 1,1′-thiocarbonyldiimidazole (0.35 g, 2 mmole),imidazole (27 mg, 0.4 mmole), and CH₃CN (15 ml) at 0° C. was added4-(5-(methyl-thio)-4-morpholinopyrimidin-2-yl)benzenamine (0.4 g, 1.32mmole) dissolved in CH₃CN (30 ml) dropwise over 10 minutes. After 10minutes, the cooling bath was removed. After 3 hours,1,2-phenylenediamine (0.285 g, 2.64 mmole) was added to the reactionmixture and the reaction mixture was heated to 50° C. for 3 hours andthen stirred at ambient temperature for 16 hours. The solvent wasremoved by evaporation. The residue was chromatographed to give thiourea(10%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 9.85 (s, 1H), 9.20 (s, 1H), 8.43 (s, 1H),8.25˜8.27 (d, 2H), 7.68˜7.70 (d, 2H), 7.09˜7.10 (d, 1H), 6.95˜6.98 (t,1H), 6.74˜6.76 (d, 1H), 6.55˜6.58 (t, 1H), 4.94 (br, 2H), 3.74˜3.76 (d,4H), 3.67˜3.69 (d, 4H), 2.49 (s, 3H)

N-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine

A suspension of1-(2-aminophenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)thiourea(60 mg, 0.132 mmole) and dicyclohexylcarbodiimide (31 mg, 0.15 mmole) inTHF (5 ml) was heated at 64° C. for 20 hr. The cooled mixture waspurified by flash chromatography to give a product (40 mg, 73%).

¹H NMR (500 MHz, DMSO-d₆): δ 11.13 (s, 1H), 9.85 (s, 1H), 8.42 (s, 1H),8.28˜8.30 (d, 2H), 7.86˜7.88 (d, 2H), 7.31˜7.37 (br, 2H), 7.01 (br, 1H),3.75˜3.76 (d, 4H), 3.69˜3.70 (d, 4H), 2.47 (s, 3H)

4-(3-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)ureido)benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (s, 1H), 8.25˜8.27 (d, 2H), 7.72˜7.74(d, 2H), 7.63˜7.65 (d, 2H), 7.59˜7.60 (d, 2H), 7.20 (s, 2H), 3.75˜3.76(d, 4H), 3.68˜3.69 (d, 4H)

1-(3,4-Dimethoxyphenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H),8.23˜8.24 (d, 2H), 7.55˜7.57 (d, 2H), 7.21 (s, 1H), 6.87˜6.88 (t, 2H),3.67˜3.76 (m, 14H), 2.47 (s, 3H)

4-(3-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)ureido)benzoicacid

¹H NMR (500 MHz, DMSO-d₆): δ 9.47 (br, 2H), 8.35 (s, 1H), 8.24˜8.25 (d,2H), 7.87˜7.88 (d, 2H), 7.63˜7.64 (d, 2H), 7.57˜7.59 (d, 2H), 3.87 (s,5H), 3.78 (s, 6H),

1-(Benzo[d][1,3]dioxol-5-yl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.05 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H)8.22˜8.24 (d, 2H), 7.54˜7.56 (d, 2H), 7.21 (s, 1H), 6.82˜6.84 (d, 1H),6.77˜6.79 (d, 1H), 5.97 (s, 2H), 3.74˜3.75 (d, 4H), 3.67˜3.68 (d, 4H),2.47 (s, 3H)

1-(5-(4-Methylpiperazin-1-yl)pyridin-2-yl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 10.57 (br, 1H), 9.29 (s, 1H), 8.42 (s, 1H)8.25˜8.27 (d, 2H), 7.95 (s, 1H), 7.61˜7.62 (d, 2H), 7.45˜7.46 (t, 2H),3.75˜3.76 (d, 4H), 3.67˜3.68 (d, 4H), 3.56 (d, 4H), 3.08 (s, 4H), 2.47(s, 3H), 2.21 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-Yl)phenyl)-3-(4-(3-oxomorpholino)phenyl)thiourea

¹H NMR (500 MHz, DMSO-d₆): δ 8.44 (s, 1H) 8.26˜8.28 (d, 2H), 7.64˜7.66(d, 2H), 7.50˜7.54 (t, 3H), 7.33˜7.35 (t, 2H), 4.19 (s, 2H), 3.97˜3.98(t, 2H), 3.67˜3.76 (m, 7H), 2.51 (s, 3H)

1-(6-Bromopyridin-3-Yl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.20˜9.25 (d, 2H), 8.48 (s, 1H), 8.41 (s,1H), 8.25˜8.26 (d, 2H), 7.90˜7.92 (d, 1H), 7.54˜7.58 (t, 3H), 3.68˜3.75(d, 8H), 2.47 (s, 3H)

1-Isopropyl-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.61 (s, 1H), 8.39 (s, 1H), 8.17˜8.19 (d,2H), 7.46˜7.48 (d, 2H), 6.14˜6.15 (d, 1H), 3.75˜3.78 (d, 5H), 3.66˜3.67(d, 4H), 2.46 (s, 3H), 1.09˜1.10 (d, 6H)

1-Tert-butyl-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.56 (br, 1H), 8.39 (s, 1H), 8.17˜8.18 (d,2H), 7.44˜7.46 (d, 2H), 6.14 (br, 1H), 3.74˜3.76 (d, 4H), 3.66˜3.67 (d,4H), 2.46 (s, 3H), 1.29 (s, 9H)

1-(4-(2-(Dimethylamino)ethoxy)phenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H),8.22˜8.24 (d, 2H), 7.54˜7.56 (d, 2H), 7.34˜7.36 (d, 2H), 6.86˜6.88 (d,2H), 3.98˜4.00 (t, 2H), 3.74˜3.76 (d, 4H), 3.67˜3.68 (d, 4H), 2.59˜2.60(d, 2H), 2.49 (s, 3H), 2.20 (s, 6H)

1,3-Bis(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.24 (s, 1H), 8.42 (s, 1H), 8.25˜8.27 (d,2H), 7.58˜7.60 (d, 2H), 3.75˜3.76 (d, 4H), 3.68˜3.69 (d, 4H)

3-Fluoro-4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)benzenamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.38 (s, 1H), 7.94˜7.98 (t, 2H), 7.53˜7.55(d, 2H), 7.39˜7.42 (m, 2H), 7.1˜7.2 (m, 3H), 3.79˜3.87 (d, 8H), 2.44 (s,3H)

N-(4-(3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)ureido)phenyl)methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ 9.45 (s, 1H), 9.16 (s, 1H), 8.98 (s, 1H),8.41 (s, 1H), 8.23˜8.25 (d, 2H), 7.56˜7.57 (d, 2H), 7.42˜7.44 (d, 2H),7.13˜7.15 (d, 2H), 3.74˜3.75 (d, 4H), 3.67˜3.68 (d, 4H), 2.91 (s, 3H),2.48 (s, 3H)

Phenyl 4-(5-(methylsulfinyl)-4-morpholinopyrimidin-2-yl)phenylcarbamate

The H₂O₂ (0.32 ml, 3.13 mmole) solution was added to a stirred solutionof phenyl 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenylcarbamate(0.54 g, 1.28 mmole), CH₂C₂ (7 ml), Ac₂O (0.13 ml), and silica gel(230˜400 mesh, 200 mg). The solution was stirred at room temperature for2˜3 hrs, and quenched with NaHSO_(3(aq)) (70 ml), and NaHCO_(3(aq)) (70ml), the solvent was removed, the residue was chromatographed to givethe product (71%) as a white solid.

¹H NMR (500 MHz, CDCl₃-d₁): δ8.97 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H),7.56˜7.58 (t, 2H), 7.39˜7.42 (t, 2H), 7.17˜7.27 (m, 3H), 3.81˜3.87 (m,6H), 3.48˜3.68 (m, 2H), 2.79 (s, 3H)

1-(4-(5-(Methylsulfinyl)-4-morpholinopyrimidin-2-yl)phenyl)-3-(4-(3-oxomorpholino)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.09 (s, 1H), 8.92 (s, 1H), 8.76 (s, 1H),8.31˜8.32 (d, 2H), 7.59˜7.61 (d, 2H), 7.48˜7.50 (d, 2H), 7.28˜7.30 (d,2H), 4.18 (s, 2H), 3.96 (d, 4H), 3.62˜3.73 (m, 10H), 2.79 (s, 3H)

1-(4-(Methylsulfonyl)phenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.61 (br, 1H), 9.33 (br, 1H), 8.42 (s, 1H),8.25˜8.27 (d, 2H), 7.81˜7.83 (d, 2H), 7.71˜7.72 (d, 2H), 7.59˜7.61 (d,2H), 3.75˜3.76 (d, 4H), 3.68˜3.69 (d, 4H), 3.15 (s, 3H)

1-(4-(4-(Methylsulfonyl)piperazin-1-yl)phenyl)-3-(4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.38 (br, 1H), 9.02 (br, 1H), 8.41 (s, 1H),8.21˜8.23 (d, 2H), 7.56˜7.58 (d, 2H), 7.35˜7.37 (d, 2H), 6.91˜6.93 (d,2H), 3.74˜3.76 (d, 4H), 3.56˜3.68 (d, 4H), 3.24˜3.25 (d, 4H), 3.15˜3.16(d, 4H), 2.92 (s, 3H), 2.47 (s, 3H)

5-(Methylthio)-4-morpholino-2,5′-bipyrimidin-2′-amine

¹H NMR (500 MHz, DMSO-d₆): δ 9.03 (s, 2H), 8.36 (s, 1H), 7.14 (s, 2H),3.72˜3.73 (d, 4H), 3.67˜3.68 (d, 4H), 2.49 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.00 (s, 1H), 8.58 (s, 1H), 8.41 (s, 1H),8.23˜8.25 (d, 2H), 7.55˜7.57 (d, 3H), 7.05˜7.07 (d, 1H), 6.97˜6.99 (d,1H), 3.74˜3.76 (d, 4H), 3.67˜3.69 (d, 4H), 2.48 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(4-(morpholine-4-carbonyl)phenyl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 8.41 (s, 1H), 8.20˜8.22 (d, 2H), 7.60˜7.66(m, 4H), 7.31˜7.33 (d, 2H), 3.74˜3.75 (d, 4H), 3.68 (s, 4H), 3.59 (s,4H), 3.50 (s, 4H), 2.48 (s, 3H)

1-(4-(5-(Methylthio)-4-morpholinopyrimidin-2-yl)phenyl)-3-(pyridin-4-yl)urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.28 (s, 1H), 8.42 (s, 1H),8.36˜8.37 (d, 2H), 8.26˜8.27 (d, 2H), 7.57˜7.58 (d, 2H), 7.44˜7.45 (d,2H), 3.75˜3.76 (d, 4H), 3.67˜3.68 (d, 4H), 2.48 (s, 3H)

Example 6 Preparation of Compounds of Formula (I) in Scheme 64-Chloro-2,6-dimethoxy-5-methylsulfanyl-pyrimidine

A mixture of 2,4,6-trichloro-5-methylsulfanyl-pyrimidine (5.00 g, 21.73mmol.) was added dropwise to a slurry of sodium methoxide (2.47 g, 45.65mmol, 2.1 eq) in MeOH (80 ml) in ice bath at 0° C., then the reactionmixture was stirred at r.t, for 2 hrs and dried, and the solvent wasevaporated. The reaction mixture was partitioned between EA and 0.1 NHCl. The organic layer was washed with brine, dried over MgSO₄, filteredand evaporated in vacuo. The resulting residue was purified by flashchromatography on silica gel (Hexane/EtOAc 9:1) to give a gray solid3.36 g (70.2%).

¹H NMR (500 MHz, CDCl₃-d₁): δ4.07 (s, 3H), 4.00 (s, 3H), 2.33 (s, 3H)

2-(2,6-Dimethoxy-5-methylsulfanyl-pyrimidin-4-yl)-malonic acid dimethylester

A mixture of 4-chloro-2,6-dimethoxy-5-methylsulfanyl-pyrimidine (3.30 g,15.0 mmol.) and dimethyl malonate (11.88 g, 90.0 mmol, 6.0 eq.) wasadded dropwise to slurry of sodium hydride (60% w/w) (3.67 g, 90.0 mmol,6.0 eq) in DMF (80 ml) in ice bath at 0° C., then the reaction mixturewas stirred at 100° C. for 10 hrs and dried, and the solvent wasevaporated. The reaction mixture was partitioned between EA and 0.1 NHCl. The organic layer was washed with brine, dried over MgSO₄, filteredand evaporated in vacuo. The resulting residue was purified by flashchromatography on silica gel (Hexane/EtOAc 6:1) to give a pale yellowoil product of 2.85 g (60.2%).

¹H NMR (500 MHz, CDCl₃-d₁): δ5.40 (s, 1H), 4.07 (s, 3H), 3.95 (s, 3H),3.80 (s, 6H), 2.23 (s, 3H)

(2,6-Dihydroxy-5-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester

A mixture of 2-(2,6-dimethoxy-5-methylsulfanyl-pyrimidin-4-yl)-malonicacid dimethyl ester (2.85 g, 9.0 mmol.) was added dropwise to slurry ofHCl (37% w/w) (1.0 ml) in MeOH (50 ml). The reaction mixture was stirredat 100° C. for 24 hr and dried, and the solvent was evaporated in vacuoto give a crude as a pale yellow solid of 1.85 g (89.2%).

¹H NMR (500 MHz, DMSO-d₆): δ11.35 (s, 1H), 11.23 (s, 1H), 3.81 (s, 2H),3.66 (s, 3H), 2.11 (s, 3H)

(2,6-Dichloro-5-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester

A mixture of (2,6-dihydroxy-5-methylsulfanyl-pyrimidin-4-yl)-acetic acidmethyl ester (1.85 g, 9.0 mmol.) was added dropwise to a slurry of POCl₃(8.0 ml). After the reaction mixture was stirred at 90° C. for 4 hrs,hydrolysis was carried out in iced salt water. The product of thereaction was extracted with EA and then evaporated to remove the EA soas to give a crude. Purification of the crude by flash chromatography onsilica gel (Hexane/EtOAc 3:1) gave a brown oil product of 866 mg(40.5%).

¹H NMR (500 MHz, CDCl₃-d₁): δ4.15 (s, 2H), 3.74 (s, 3H), 2.39 (s, 3H)

(2-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl)-acetic acidmethyl ester

A mixture of (2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-acetic acidmethyl ester (860 mg, 3.22 mmol.), morpholine (336 mg, 3.86 mmol, 1.2eq.) and THF (10 ml) was stirred at room temperature for 2.0 hrs. Thereaction mixture was dried and the solvent was evaporated. The reactionmixture was subjected to addition of 0.1 N HCl washing free morpholine,extraction with EA and evaporation to remove the EA so as to give acrude. Purification of the crude by flash chromatography on silica gel(Hexane/EtOAc 2:1) gave a gray solid of 427 mg (42.7%).

¹H NMR (500 MHz, CDCl₃-d₁): δ3.99 (s, 2H), 3.80 (dd, 4H), 3.73 (dd, 4H),3.71 (s, 3H), 2.21 (s, 3H)

[2-(4-Amino-phenyl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-aceticacid methyl ester

A mixture of(2-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl)-acetic acidmethyl ester (420 mg, 1.47 mmol.),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline) (357 mg, 1.62mmol.), (PPh₃)₄Pd (170 mg, 0.07 mmol.), 2M Na₂CO₃ (2.2 ml, 4.14 mmol,3.0 eq.) and dioxane (10 ml) was added a reaction vessel which wasflushed with argon. The reaction mixture was stirred at 90° C. for 12 hrthen dried, and the solvent was evaporated. The reaction mixture waspartitioned between EA and water, the organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated in vacuo. The resultingresidue was purified by flash chromatography on silica gel (Hexane/EtOAc3:2) to give a pale yellow solid of 424 mg (43.8%).

¹H NMR (500 MHz, DMSO-d₆): δ7.75 (dd, 2H), 6.70 (dd, 2H), 4.05 (s, 2H),3.84 (s, 3H), 3.74 (d, 8H), 1.91 (s, 3H)

{5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid methyl ester

A mixture of[2-(4-amino-phenyl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-aceticacid methyl ester (400 mg, 1.06 mmol.), phenyl isocyanate (254 mg, 2.13mmol, 2.0 eq) and CH₂Cl₂ (1.0 ml), toluene (2.0 ml) was added a reactionvessel which was flushed with argon. The reaction mixture was stirred at90° C. for 16 hrs. After cooling and filtering, the precipitate waswashed with a minor portion of CH₂Cl₂ again to give a white solid 316 ofmg (60.1%).

¹H NMR (500 MHz, DMSO-d₆): δ8.89 (s, 1H), 8.74 (s, 1H), 7.73 (d, 2H),7.54 (d, 2H), 7.47 (d, 2H), 7.29 (dd, 2H), 6.98 (d, 1H), 4.02 (s, 2H),3.73 (d, 4H), 3.66 (d, 4H), 3.65 (s, 3H), 2.08 (s, 3H)

{5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid sodium salt

1N NaOH (1.0 ml, 6.0 eq.) was added to a stirred solution of {5-methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid methyl ester (80 mg, 0.16 mmol.) in MeOH (2.0 ml) and the mixturewas refluxed for 4 hrs. The mixture was cooled to r.t. and filtered. Theprecipitate was washed with MeOH and dried in vacuo to give a whitesolid of 61 mg (75.2%).

¹H NMR (500 MHz, DMSO-d₆): δ7.59 (d, 2H), 7.48 (d, 2H), 7.38 (d, 2H),7.00 (t, 2H), 6.54 (t, 1H), 3.69 (dd, 8H), 1.96 (s, 3H)

5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid

1N NaOH (1.0 ml, 6.0 eq.) was added to a stirred solution of {5-methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid methyl ester (80 mg, 0.16 mmol.) in MeOH (2.0 ml) and the mixturewas refluxed at 0° C. and carefully acidified with conc. HCl. Themixture was filtered and the precipitate was dried in vacuo to give awhite solid 64 mg (84.2%).

¹H NMR (500 MHz, DMSO-d₆): δ9.00 (s, 1H), 8.76 (s, 1H), 7.72 (d, 2H),7.65-7.46 (m, 4H), 7.29 (t, 2H), 6.99 (t, 1H), 3.93 (s, 2H), 3.72 (d,4H), 3.65 (d, 4H), 2.08 (s, 3H)

Example 7 Preparation of Formula (I) in Scheme 76-Hydroxy-5-methoxy-1H-pyrimidine-2,4-dione

The NaOCH₃ (8.5 g, 157 mmole), was added to a stirred solution ofdimethyl 2-methoxymalonate (10.2 g, 62.91 mmole), urea (2.5 g, 41.7mmole), and EtOH (80 ml). The reaction mixture was heated to 100° C. for4 hrs, then the reaction was evaporated to remove the solvent. Water wasadded to the mixture and then concentrated HCl was added. The pH of themixture was adjusted to ca. 3˜4. The mixture was filtered and wash waterand acetone. After drying in vacuo, it gave a product (99%).

¹H NMR (500 MHz, DMSO-d₆): δ 8.74 (s, 1H), 3.23 (s, 3H)

2,4,6-Trichloro-5-methoxyprimidine

¹H NMR (500 MHz, CDCl₃-d₁): δ3.97 (s, 3H)

4-(2,6-Dichloro-5-methoxypyrimidin-4-yl)morpholine

¹H NMR (500 MHz, CDCl₃-d₁): δ3.87˜3.89 (d, 4H), 3.76˜3.78 (d, 4H), 3.73(s, 3H)

4-(4-chloro-5-methoxy-6-morpholinopyrimidin-2-yl)benzenamine

¹H NMR (500 MHz, DMSO-d₆): δ 7.90˜7.91 (d, 2H), 6.56˜6.58 (d, 2H), 5.65(br, 2H), 3.79 (s, 4H), 3.73 (s, 4H), 3.67 (s, 3H)

1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ 9.28 (s, 1H), 9.23 (s, 1H), 8.36˜8.37 (d,2H), 8.15˜8.17 (d, 2H), 7.56˜7.58 (d, 2H), 7.44˜7.46 (d, 2H), 3.84˜3.86(d, 4H), 3.74˜3.75 (d, 4H), 3.71 (s, 3H)

5-Ethoxy-6-hydroxy-1H-pyrimidine-2,4-dione

¹H NMR (500 MHz, DMSO-d₆): δ1.06-1.09 (m, 3H), 3.58-3.61 (m, 2H), 9.00(s, 2H)

2,4,6-Trichloro-5-ethoxy-pyrimidine

¹H NMR (500 MHz, CDCl3-d): δ1.47-1.50 (m, 3H), 4.17-4.21 (m, 2H)

4-(2,6-Dichloro-5-ethoxy-pyrimidin-4-yl)-morpholine

¹H NMR (500 MHz, CDCl₃-d₁): δ1.38-1.40 (m, 3H), 3.76-3.78 (m, 4H),3.87-3.89 (m, 4H), 3.91-3.95 (m, 2H)

4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl3-d₁): δ1.38-1.41 (m, 3H), 3.81-3.83 (m, 4H),3.87-3.89 (m, 4H), 3.94-3.98 (m, 2H), 6.72-6.73 (m, 2H), 8.12-8.14 (m,2H)

1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.31-1.34 (m, 3H), 3.73-3.75 (m, 4H),3.84-3.86 (m, 4H), 3.92-3.96 (m, 4H), 7.45-7.46 (m, 2H), 7.57-7.59 (m,2H), 8.16-8.18 (m, 2H), 8.37-8.38 (m, 2H), 9.17 (s, 1H), 9.20 (s, 1H)

1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.31-1.34 (m, 3H), 3.73-3.75 (m, 4H),3.84-3.86 (m, 4H), 3.92-3.96 (m, 2H), 7.33-7.34 (m, 1H), 7.56-7.58 (m,2H), 7.95-7.97 (m, 1H), 8.15-8.17 (m, 2H), 8.21 (m, 1H), 8.62 (s, 1H),8.92 (s, 1H), 9.10 (s, 1H)

Example 8 Preparation of Compounds of Formula (I) in Scheme 85-Methoxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one

A mixture of methyl methoxy acetate (5 mL, 1.0 eq) and ethyl formate(4.07 mL, 1.0 eq) was added dropwise to a slurry of sodium methoxide(5.45 g, 2.0 eq) in toluene (20 mL) in ice both. After dropping at roomtemperature and stirring overnight, the resulting solution was dried invacuo. Then a mixture of residue, 4-nitrobenzimide (10.17 g, 1.0 eq) andsodium methoxide (2.72 g, 1.0 eq) in EtOH (80 mL) was refluxed at 110°C. for 6 hrs. After the solvent was dried in vacuo, water and conc. HClsolution (5<pH<4) were added. After formation of white precipitates, themixture was filtered and dried solid in vacuo. A product was obtained asa white solid (3.21 g, 26%).

4-Chloro-5-methoxy-2-(4-nitro-phenyl)-pyrimidine

In ice bath, dimethyl-phenyl-amine (1.19 mL, 1.0 eq) was added dropwiseto a slurry of 5-Methoxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one (2.3 g,1.0 eq) in POCl₃ (4.4 mL, 5.0 eq) and the mixture was refluxedovernight. Excess POCl₃ was evaporated in vacuo and the residue waspoured into ice-water. After formation of precipitates, the mixture wasfiltered and the residue was dried solid in vacuo. A product wasobtained as a white solid (2.47 g, 61%).

4-[5-Methoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine

4-chloro-5-methoxy-2-(4-nitro-phenyl)-pyrimidine (1.50 g, 1.0 eq) wasstirred in dichloromethane (10 mL) and a solution of morpholine (0.75mL, 1.5 eq) in dichloromethane (5 mL) was added dropwise to the mixtureat 0° C. After stirring, the resulting solution was reacted overnight atr.t., NH₄Cl (aq) was added to the solution and the solution wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried and evaporated in vacuo. A product was obtained as awhite solid (0.73 g, 41%).

¹H NMR (500 MHz, DMSO-d₆): δ 3.74 (s, 4H), 3.80 (s, 4H), 3.93 (s, 3H),8.24 (s, 1H), 8.30 (d, 2H), 8.48 (d, 2H)

4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

4-[5-methoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2 g, 1 eq)was stirred under hydrogen balloon with palladium on carbon (10 percent,0.1 g, 0.15 eq) in a mixture of MeOH and EA (1:1, 8 mL) at roomtemperature overnight. The reaction mixture was then filtered throughCelite, volatiles were removed in vacuo, and the residue was purified byflash chromatography to give a white solid (0.15 g, 83%).

¹H NMR (500 MHz, DMSO-d₆): δ 3.71 (s, 8H), 3.83 (s, 3H), 5.54 (s, 2H),6.58 (d, 2H), 7.95 (d, 2H), 8.04 (s, 1H)

6-Hydroxy-5-methoxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one

The NaOCH₃ (7.8 g, 3 eq) was added to a stirred solution of 1-ethyl3-methyl 2-methoxymalonate (11 g, 1.3 eq), 4-nitrobenzimidamidehydrochloride (9.6 g, 1 eq) and EtOH (240 ml) and the mixture wasrefluxed for 8 hrs. After 8 hrs, the solvent was evaporated and water(10˜15 ml) was added to the mixture then the mixture was cooled to 0° C.and carefully acidified with conc. HCl. After overnight cooling, it ledto the formation of brown precipitates. The mixture was filtered and theprecipitates was dried in vacuo to give a brown solid (65%) as aproduct.

¹H NMR (500 MHz, DMSO-d₆): δ3.71 (s, 3H), 8.28˜8.35 (m, 4H)

4,6-Dichloro-5-methoxy-2-(4-nitro-phenyl)-pyrimidine

The POCl₃ (30 ml, 16.7 eq) was added to a stirred solution of5-methoxy-2-(4-nitrophenyl)pyrimidine-4,6-diol (5.13 g, 1 eq) andN,N-dimethylaniline (3.2 ml, 1.27 eq) the mixture was refluxedovernight. Excess POCl₃ was evaporated in vacuo and the residue waspoured into ice-water to give a solid. The solid was filtered and driedin vacuo to given a brown solid (81%) as a product.

¹H NMR (500 MHz, CDCl₃-d₁): δ4.03 (s, 3H), 8.31˜8.32 (d, 2H), 8.54˜8.56(d, 2H)

4-[6-Chloro-5-methoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine

Morpholine (0.6 ml, 2.2 eq) was added to a stirred solution of4,6-dichloro-5-methoxy-2-(4-nitrophenyl)pyrimidine (0.87 g, 1 eq) inTHF, the mixture was stirred at r.t for 4 hrs, the solvent wasevaporated, water was added to the solution and the solution wasextracted with EA. The combined organic layers were washed with brine,dried and evaporated in vacuo, the product was obtained as a yellowsolid (56%).

¹H NMR (500 MHz, CDCl₃-d₁): δ3.08 (s, 3H), 3.84˜3.86 (d, 4H), 3.93˜3.94(d, 4H), 8.26˜8.27 (d, 2H), 8.46˜8.47 (d, 2H)

4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

To a stirring solution of 4-(6-chloro-5-methoxy-2-(4-nitrophenyl)yrimidin-4-yl)morpholine (200 mg, 1 eq), and acetic acid (1 ml) in a 25ml single-necked round-bottomed flask equipped with a magnetic stirrerwas added Zn dust (78 mg, 2.1 eq). The mixture was stirred at ambienttemperature for 1 hr. The mixture was poured into a solution ofsaturated NaHCO₃ (34 ml). The mixture was filtered and partitionedbetween CH₂Cl₂ and water. The organic portion was dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by silicagel to obtain a product (45%),

¹H NMR (500 MHz, DMSO-d₆): δ3.67 (s, 3H), 3.73 (d, 4H), 3.79 (d, 4H),5.65 (s, 2H), 6.56˜6.58 (d, 2H), 7.90˜7.91 (d, 2H)5-Ethoxy-6-hydroxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one

A mixture of 4-nitrobenzimide (8.0 g, 1.0 eq) and 2-ethoxy-malonic aciddiethyl ester (10.54 g, 1.3 eq) and sodium methoxide (6.43 g, 3.0 eq) inEtOH (140 mL) was refluxed at 80° C. for 6 hrs. After the solvent wasdried in vacuo, water and cone. HCl solution (5<pH<4) were added. Afterformation of white precipitates, the mixture was filtered and driedsolid in vacuo. A product was obtained as a white solid (1.85 g, 26%).

4,6-Dichloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidine

In ice bath, dimethyl-phenyl-amine (0.94 mL, 1.1 eq) was added dropwiseto a slurry of 5-ethoxy-6-hydroxy-2-(4-nitro-phenyl)-3H-pyrimidin-4-one(1.85 g, 1.0 eq) in POCl₃ (6.5 mL, 10.32 eq) and the resulting solutionwas refluxed overnight. Excess POCl₃ was evaporated in vacuo and theresidue was poured into ice-water. After formation of precipitates, themixture was filtered and dried solid in vacuo. A product was obtained asa white solid (0.5 g, 24%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.42 (t, 3H), 4.25 (q, 2H), 8.39 (d, 2H),8.48 (d, 2H)

4-[6-Chloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine

4,6-dichloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidine (0.50 g, 1.0 eq) wasstirred in dichloromethane (10 mL) and a solution of morpholine (0.21mL, 1.5 eq) in dichloromethane (5 mL) was added dropwise at 0° C. Afterstirring the resulting solution overnight at r.t., NH₄Cl(aq) was addedto the solution and the solution was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried and evaporated invacuo. A product was obtained as a white solid (0.57 g, 81%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.34 (t, 3H), 3.76 (t, 4H), 3.89 (t, 4H),3.98 (q, 2H), 8.32 (d, 2H), 8.45 (d, 2H)

4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

4-[6-chloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2g, 1 eq) was stirred under hydrogen balloon with platinum on carbon (10percent, 0.11 g, 0.1 eq) in a mixture of MeOH and EA (1:1, 8 mL) at roomtemperature overnight. The reaction mixture was then filtered throughCelite, the volatiles in the mixture was removed in vacuo, and theresidue was purified by flash chromatography to give a white solid (0.13g, 83%).

¹H NMR (500 MHz, CDCl₃-d₁): δ1.41 (t, 3H), 3.81 (t, 4H), 3.88 (t, 4H),3.96 (q, 2H), 6.75 (d, 2H), 8.14 (d, 2H)

Example 9 Preparation of Compounds of Formula (I) in Scheme 92-Chloro-5-methoxy-4-pyridin-4-yl-pyrimidine

A mixture of 2,4-dichloro-5-methoxy-pyrimidine (3.0 g, 1.0 eq.),4-pyridinylboronic acid (2.26 g, 1.1 eq.), Pd(PPh₃)₂Cl₂ (0.58 g, 0.05eq.), K₃PO₄.H₂O (10.67 g, 3.0 eq.), H₂O (3 ml) and 1,4-Dioxane (20.0 ml)was heated at 90° C. and refluxed overnight. The solvent was removed invacuo, and the residue was extracted with EA and water. The combinedorganic layers was wash with brine, dried and evaporated in vacuo. Thecrude was purified by chromatography to give a yellow thick liquid (1.83g, 49.26%).

¹H NMR (500 MHz, CDCl3-d₁): δ8.76-8.75 (d, 2H), 8.42 (s, 1H), 8.02-8.04(d, 2H), 4.05 (s, 3H).

4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl3-d₁): δ8.75-8.76 (m, 2H), 8.55 (s, 1H), 8.26-8.28(d, 2H), 8.15-8.17 (m, 2H), 6.76-6.78 (d, 2H), 4.00 (s, 3H).

[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acidphenyl ester

¹H NMR (500 MHz, CDCl3-d₁): δ8.78-8.79 (d, 2H), 8.61 (s, 1H), 8.44-8.45(d, 2H), 8.22-8.23 (d, 2H), 7.59-7.60 (d, 2H), 7.40-7.43 (m, 2H),7.21-7.27 (m, 3H), 7.13 (s, 1H), 4.08 (s, 3H).

1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.94-9.58 (m, 2H), 8.87 (s, 1H), 8.76-8.78(m, 2H), 8.32-8.34 (m, 2H), 8.12-8.13 (m, 2H), 7.63-7.67 (m, 2H),7.55-7.56 (m, 2H), 7.38-7.37 (m, 2H), 4.07 (s, 3H), 3.60 (s, 4H), 3.50(s, 4H).

1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.32 (s, 1H), 9.12 (s, 1H), 8.86-8.87 (m,1H), 8.76-8.78 (m, 2H), 8.31-8.34 (m, 2H), 8.12-8.13 (m, 2H), 7.64-7.67(m, 2H), 7.50-7.52 (m, 2H), 7.28-7.30 (m, 2H), 4.18 (s, 2H), 4.07 (s,3H), 3.95-3.97 (m, 2H), 3.69-3.71 (m, 2H).

1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.72 (s, 1H), 9.45 (s, 1H), 8.87 (s, 1H),8.77-8.78 (m, 2H), 8.33-8.37 (m, 4H), 8.12-8.13 (m, 2H), 7.63-7.65 (d,2H), 7.46-7.48 (d, 2H), 4.07 (s, 3H).

Example 10 Preparation of Compounds of Formula (I) in Scheme 10[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ8.76-8.73 (d, 2H), 8.45-8.43 (d, 2H),7.71-7.68 (m, 2H), 7.57-7.55 (d, 2H), 7.42-7.39 (m, 2H), 7.27-7.20 (m,3H), 3.91-3.90 (s, 8H), 1.62 (s, 3H)

4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ8.73-8.72 (d, 2H), 8.28-8.26 (d, 2H),7.69-7.67 (dd, 2H), 6.72-6.71 (s, 2H), 3.95 (s, 2H), 3.89 (s, 8H), 2.04(s, 3H)

[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.85 (s, 1H), 8.72-8.71 (d, 2H), 8.24-8.22(d, 2H), 7.68-7.67 (d, 2H), 7.52-7.50 (d, 2H), 5.96 (s, 2H), 3.87-3.86(d, 4H), 3.80-3.79 (d, 4H), 2.05 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.24 (s, 1H), 9.06 (s, 1H), 8.72-8.71 (d,2H), 8.29-8.28 (d, 2H), 7.69-7.68 (dd, 2H), 7.61-7.59 (d, 2H), 7.51-7.49(d, 2H), 7.29-7.27 (d, 2H) 4.18 (s, 2H), 3.96-3.94 (d, 2H), 3.88-3.87(d, 4H), 3.81-3.80 (d, 4H), 3.70-3.68 (d, 2H), 2.05 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.34 (s, 1H), 9.29 (s, 1H), 8.73-8.72 (d,2H), 8.38-8.37 (d, 2H), 8.33-8.31 (d, 2H), 7.69-7.68 (d, 2H), 7.61-7.59(d, 2H), 7.48-7.46 (d, 2H), 3.88-3.87 (d, 4H), 3.81-3.80 (d, 4H), 2.06(s, 3H)

4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide

¹H NMR (500 MHz, DMSO-d₆): δ9.40 (b, 1H), 9.34 (b, 1H), 8.72-8.71 (d,2H), 8.29-8.27 (d, 2H), 7.82-7.80 (d, 3H), 7.69-7.67 (d, 2H), 7.63-7.61(d, 2H), 7.56-7.54 (d, 2H), 7.14 (s, 1H), 3.87-3.86 (d, 4H), 3.81-3.80(d, 4H), 2.05 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.07 (s, 1H), 8.83 (s, 1H), 8.73-8.72 (d,2H), 8.30-8.29 (d, 2H), 7.69-7.68 (d, 2H), 7.59-7.58 (d, 2H), 7.47-7.46(d, 2H), 7.30-7.27 (d, 2H), 6.98 (s, 1H), 3.88-3.87 (d, 4H), 3.81-3.80(d, 4H), 2.05 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ10.0 (b, 1H), 9.99 (b, 1H), 8.73-8.72 (d,2H), 8.32-8.30 (d, 2H), 7.70-7.66 (m, 4H), 7.50-7.49 (d, 2H), 7.35-7.32(d, 2H), 7.15-7.12 (d, 1H), 3.89-3.88 (d, 4H), 3.81-3.80 (d, 4H), 2.04(s, 3H)

1-Ethyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.75 (s, 1H), 8.72-8.71 (d, 2H), 8.24-8.22(d, 2H), 7.68-7.67 (d, 2H), 7.52-7.50 (d, 2H), 6.22-6.19 (t, 1H),3.87-3.86 (d, 4H), 3.80-3.79 (d, 4H), 3.13-3.10 (dd, 2H), 2.05 (s, 3H),1.07-1.04 (t, 3H)

1-Methyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.90 (s, 1H), 8.72-8.71 (d, 2H), 8.24-8.22(d, 2H), 7.68-7.67 (d, 2H), 7.52-7.51 (d, 2H), 6.18-6.17 (d, 1H),3.87-3.86 (d, 4H), 3.79 (d, 4H), 2.65 (s, 3H), 2.05 (s, 3H)

1-Isopropyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.72-8.71 (d, 2H), 8.62 (s, 1H), 8.24-8.22(d, 2H), 7.68-7.67 (d, 2H), 7.50-7.48 (d, 2H), 6.11-6.10 (d, 1H),3.87-3.86 (d, 4H), 3.77-3.74 (d, 4H), 2.05 (s, 3H), 1.11-1.10 (t, 6H),1.00-0.99 (d, 1H)

1-Isoxazol-3-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.74 (s, 1H), 9.22 (s, 1H), 8.75-8.72 (m,3H), 8.32-8.29 (d, 2H), 7.69-7.68 (d, 2H), 7.62-7.58 (d, 2H), 6.87-6.87(d, 1H), 3.88-3.87 (d, 4H), 3.81-3.80 (s, 4H), 2.06 (s, 3H)

4-(5-Methylsulfanyl-4,6-di-morpholin-4-yl-pyrimidin-2-yl)-phenylamine

A mixture of4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(200 mg, 0.594 mmol.), morpholin (103 mg, 1.118 mmol, 2.0 eq),triethylamine (120 mg, 1.118 mmol, 2.0 eq) in dioxane (8 ml) and themixture was reacted for 16 hrs at 90° C. The reaction mixture was driedand the solvent was removed by evaporation in vacuo. The reactionmixture was partitioned between EA and water. The organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated in vacuo.The resulting residue was purified using flash chromatography on silicagel (EA), and recrystallized by (Hexane/EtOAc) to give a gray white 106mg (46.1%).

¹H NMR (500 MHz, CDCl₃-d₁): δ8.19-8.17 (d, 2H), 6.69-6.68 (d, 2H), 3.88(s, 2H), 3.84-3.82 (d, 8H), 3.69-3.68 (d, 8H), 2.2 (s, 3H)

1-{4-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea

A mixture of1-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(120 mg, 0.26 mmol.), 1-methanesulfonyl-piperazine (65 mg, 0.39 mmol,1.5 eq.), triethylamine (40 mg, 0.39 mmol, 1.5 eq.), and DMF (4.0 mil)was added to the reaction vessel and flushed with argon. The reactionmixture was stirred at 80° C. for 5 hrs and then dried, and the solventwas evaporated. The reaction mixture was partitioned between EA andNH₄Cl_((aq)), the organic layer was washed with brine, dried over MgSO₄,filtered and evaporated in vacuo. The resulting residue was purifiedwith flash chromatography on silica gel (Hexane/EtOAc 1:1) to give apale yellow solid of 77.2 mg (50.3%).

¹H NMR (500 MHz, DMSO-d₆): δ8.87 (s, 1H), 8.73 (s, 1H), 7.57-7.50 (m,5H), 7.29 (t, 2H), 6.98 (t, 1H), 3.85 (d, 4H), 3.79 (d, 8H), 3.20 (d,4H), 2.90 (s, 3H), 1.93 (s, 3H)

1-{4-[4-(4-Methyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.21 (s, 1H), 9.07 (s, 1H), 8.60 (s, 1H),8.21-8.18 (m, 3H), 7.95 (s, 1H), 7.55-7.53 (d, 2H), 7.31 (d, 1H), 3.72(b, 4H), 3.60 (s, 8H), 2.44 (b, 4H), 2.21 (s, 3H), 2.14 (s, 3H)

4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, CDCl₃-d₁): δ9.02-9.02 (d, 1H), 8.68-8.67 (dd, 1H),8.29-8.28 (dd, 2H), 8.14-8.12 (dd, 1H), 7.41-7.38 (s, 1H), 6.73-6.71 (d,2H), 3.94 (s, 2H), 3.90 (s, 8H), 2.04-2.03 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea

¹H NMR (500 MHz, DMSO-d₆): δ8.98 (s, 1H), 8.91-8.90 (d, 1H), 8.74 (s,1H), 8.69-8.67 (dd, 1H), 8.33-8.31 (d, 2H), 8.16-8.14 (d, 1H), 7.60-7.58(m, 3H), 7.56-7.53 (dd, 2H), 7.47-7.27 (dd, 2H), 6.98 (s, 1H), 3.88-3.87(d, 4H), 3.81-3.80 (d, 4H), 2.04 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea

¹H NMR (500 MHz, DMSO-d₆): δ10.03 (s, 1H), 9.93 (s, 1H), 8.91-8.91 (d,1H), 8.68-8.67 (dd, 1H), 8.34-8.32 (d, 2H), 8.16-8.154 (d, 1H),7.68-7.66 (d, 2H), 7.55-7.49 (m, 3H), 7.36-7.33 (d, 2H), 7.15-7.14 (d,1H), 3.89-3.88 (d, 4H), 3.81-3.80 (d, 4H), 2.04 (s, 3H)

[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, CDCl₃-d₁): δ9.06-9.05 (d, 1H), 8.71-8.70 (d, 1H),8.46-8.44 (d, 2H), 8.17-8.15 (dd, 1H), 7.58-7.56 (d, 2H), 7.43-7.41 (d,3H), 7.41-7.39 (d, 1H), 7.27-7.20 (m, 3H), 3.92-3.92 (d, 8H), 2.05-2.04(s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.05 (s, 1H), 8.90-8.87 (d, 2H), 8.68-8.67(d, 1H), 8.33-8.31 (d, 2H), 8.16-8.14 (d, 1H), 7.60-7.56 (m, 3H),7.55-7.48 (dd, 2H), 7.30-7.28 (d, 2H), 4.18 (s, 2H), 3.97-3.95 (d, 2H),3.88-3.87 (d, 4H), 3.81-3.80 (d, 4H), 3.70-3.68 (d, 2H), 2.04 (s, 3H)

1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ9.21 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H),8.68-8.67 (d, 1H), 8.62 (d, 1H), 8.33-8.31 (d, 2H), 8.21-8.20 (d, 1H),8.15-8.14 (d, 1H), 7.97-7.95 (d, 1H), 7.61-7.54 (dd, 2H), 7.34-7.33 (d,2H), 3.88 (s, 4H), 3.81 (s, 4H), 2.04 (s, 3H)

N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide

¹H NMR (500 MHz, DMSO-d₆): δ9.34 (b, 1H), 9.05 (s, 1H), 8.90 (s, 1H),8.82 (s, 1H), 8.67 (s, 1H), 8.32-8.30 (d, 2H), 8.15-8.14 (d, 1H),7.59-7.57 (d, 2H), 7.54 (s, 1H), 7.44-7.42 (d, 2H), 7.15-7.14 (d, 2H),3.87 (s, 4H), 3.80 (s, 4H), 2.91 (s, 3H), 2.04 (s, 3H)

4-(5-Methylsulfanyl-2,6-di-pyridin-3-yl-pyrimidin-4-yl)-morpholine

A mixture of 4-(2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-morpholine(200 mg, 0.717 mmol.),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (323 mg, 1.577mmol, 2.2 eq), (PPh₃)₄Pd (165 mg, 0.2 mmol.), 2M Na₂CO₃ (2.1 ml, 4.302mmol, 6.0 eq.) and dioxane (20 ml) was added to a reaction vessel whichwas then flushed with argon. The reaction mixture was stirred at 90° C.for 16 hrs, and then dried. The solvent was removed by evaporation. Themixture was partitioned between EA and water. The organic layer wascollected, washed with brine, dried over MgSO₄, filtered and evaporatedin vacuo. The resulting residue was purified using flash chromatographyon silica gel (Hexane/EtOAc 2:3, few Et3N), recrystallized by(Hexane/EtOAc) to give a pale yellow solid 57.8 mg (22.1%).

¹H NMR (500 MHz, CDCl₃-d₁): δ9.52-9.51 (d, 1H), 8.94-8.94 (d, 1H),8.70-8.66 (m, 3H), 8.19-8.18 (d, 1H), 7.57-7.53 (dd, 2H), 3.92-3.90 (d,4H), 3.81-3.80 (d, 4H), 2.05 (s, 3H)

4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, DMSO-d₆): δ1.07-1.10 (m, 3H), 3.66-3.70 (m, 2H),3.78-3.79 (m, 8H), 5.54 (s, 2H), 6.60-6.62 (m, 2H), 7.52-7.54 (m, 1H),8.06-8.07 (m, 2H), 8.36-8.38 (m, 1H), 8.65-8.66 (m, 1H), 9.17 (s, 1H)

4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine

¹H NMR (500 MHz, DMSO-d₆): δ1.09-1.13 (m, 3H), 3.67-3.71 (m, 2H),3.78-3.79 (m, 8H), 5.55 (s, 2H), 6.60-6.62 (m, 2H), 7.97-7.98 (m, 2H),8.05-8.07 (m, 2H), 8.71-8.73 (m, 2H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.08-1.11 (m, 3H), 3.69-3.73 (m, 2H),3.79-3.80 (m, 4H), 3.84-3.85 (m, 4H), 7.46-7.47 (m, 2H), 7.56-7.60 (m,3H), 8.30-8.32 (m, 2H), 8.37-8.41 (m, 3H), 8.67-8.68 (m, 1H), 9.20 (s,1H), 9.24 (s, 1H), 9.32 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.08-1.11 (m, 3H), 3.69-3.73 (m, 2H),3.79-3.80 (m, 4H), 3.84-3.85 (m, 4H), 7.33 (m, 1H), 7.57-7.59 (m, 3H),7.98 (m, 1H), 8.20-8.21 (m, 1H), 8.29-8.31 (m, 2H), 8.39 (m, 1H),8.61-8.62 (m, 1H), 8.67-8.68 (m, 1H), 8.89 (s, 1H), 9.07 (s, 1H),9.19-9.20 (m, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.11-1.14 (m, 3H), 3.70-3.74 (m, 2H),3.78-3.79 (m, 4H), 3.84-3.85 (m, 4H), 7.45-7.46 (m, 2H), 7.58-7.59 (m,2H), 7.99-8.00 (m, 2H), 8.30-8.32 (m, 2H), 8.37-8.38 (m, 2H), 8.74-8.75(m, 2H), 9.20 (s, 1H), 9.25 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.11-1.14 (m, 3H), 3.70-3.74 (m, 2H),3.79-3.80 (m, 4H), 3.84-3.85 (m, 4H), 7.32-7.34 (m, 1H), 7.58-7.59 (m,2H), 7.95-8.00 (m, 3H), 8.20-8.21 (m, 1H), 8.29-8.31 (m, 2H), 8.61-8.62(m, 1H), 8.74-8.75 (m, 2H), 8.89 (s, 1H), 9.07 (s, 1H)

[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.31-1.34 (m, 3H), 3.73-3.75 (m, 4H),3.84-3.86 (m, 4H), 3.91-3.96 (m, 4H), 7.24-7.29 (m, 3H), 7.43-7.46 (m,2H), 7.61-7.63 (m, 2H), 8.18-8.20 (m, 2H)

[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.11-1.13 (m, 3H), 3.70-3.74 (m, 2H),3.78-3.79 (m, 4H), 3.84-3.85 (m, 4H), 7.24-7.29 (m, 3H), 7.43-7.46 (m,2H), 7.62-7.64 (m, 2H), 7.99-8.00 (m, 2H), 8.32-8.34 (m, 2H), 8.73-8.74(m, 2H), 10.46 (s, 1H)

[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester

¹H NMR (500 MHz, DMSO-d₆): δ1.08-1.11 (m, 3H), 3.69-3.73 (m, 2H),3.78-3.79 (m, 4H), 3.84-3.85 (m, 4H), 7.24-7.29 (m, 3H), 7.43-7.46 (m,2H), 7.53-7.57 (m, 1H), 7.62-7.64 (m, 2H), 8.32-8.34 (m, 2H), 8.39-8.41(m, 1H), 8.66-8.67 (m, 1H), 9.20 (s, 1H), 10.45 (s, 1H)

1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.31-1.34 (m, 3H), 3.68-3.70 (m, 2H),3.73-3.75 (m, 4H), 3.83-3.84 (m, 4H), 3.91-3.97 (m, 4H), 4.18 (s, 2H),7.28-7.30 (m, 2H), 7.48-7.49 (m, 2H), 7.55-7.57 (m, 2H), 8.14-8.16 (m,2H), 8.84 (s, 1H), 9.00 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.11-1.14 (m, 3H), 3.68-3.74 (m, 4H),3.78-3.79 (m, 4H), 3.84-3.85 (m, 4H), 3.95-3.97 (m, 2H), 4.18 (s, 2H),7.28-7.30 (m, 2H), 7.48-7.50 (m, 2H), 7.57-7.59 (m, 2H), 7.99-8.00 (m,2H), 8.28-8.30 (m, 2H), 8.73-8.74 (m, 2H), 8.83 (s, 1H), 8.98 (s, 1H)

1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea

¹H NMR (500 MHz, DMSO-d₆): δ1.08-1.11 (m, 3H), 3.69-3.73 (m, 4H),3.78-3.79 (m, 4H), 3.84-3.85 (m, 4H), 3.95-3.97 (m, 2H), 4.18 (s, 2H),7.28-7.30 (m, 2H), 7.48-7.50 (m, 2H), 7.54-7.58 (m, 3H), 8.28-8.30 (m,2H), 8.39-8.41 (m, 1H), 8.66-8.67 (m, 1H), 8.84 (s, 1H), 8.98 (s, 1H),9.19-9.20 (m, 1H)

Biological Testing

The compounds of the invention, prepared as described in the examples,were subject to the following series of biological assays. Briefdescriptions of different assays are as follows.

(1) Antiproliferation Assay

A549, HCT-116, and A498 cell lines were purchased from the BioresourceCollection and Research Center (BCRC, Taiwan) and cultured in Dulbecco'sModified Eagle Medium (DMEM, Sigma) containing 10% fetal bovine serum(FBS, HyClone). PC-3, U-87 MG, HCC1954 and BT474 cell lines werepurchased from the American Type Culture Collection (ATCC, USA). PC-3was grown in F12K medium (GIBCO) containing 10% FBS. U-87 MG was grownin Eagle's minimum essential medium (MEM, Sigma) supplemented withnonessential amino acids, L-glutamine, sodium pyruvate, and 10% FBS.HCC1954 was grown in RPMI medium (GIBCO) containing 10% FBS. BT-474 wasgrown in DMEM medium (GIBCO) containing 10% FBS. All cells wereincubated in a humidified atmosphere containing 5% CO₂ at 37° C.

Cell lines were inoculated to the wells of a 96-well culture plate with1000-5000 cells per well. The compounds were prepared and used to treatcells with less than 1% DMSO. After 72 hours of drug treatment, theviability of each cell line was examined by CellTiter 96 AqueousNon-Radioactive Cell Proliferation Assay (Promega). The living cellswere detectable by conversion of MTS into aqueous, soluble formazan.MTS/PMS solution was freshly prepared and 20 μl of MTS/PMS solution wasadded to each well of the 96-well cultured plate. The assay plate wasincubated for 3 hours and the absorbance at 490 nm was measured by EMaxELISA Reader (Molecular Devices). The IC₅₀ values of compounds weredetermined after carrying out assays at eight serially dilutedconcentrations of each compound in triplicate, and are the mean of threeseparate determinations. The results were analyzed using linearregression software (GraphPad Prism 5; GraphPad Software Inc.).

(2) Immunoblotting

For immunoblotting experiments, A549 cells were inoculated to the wellsof a 6-well culture plate and cultured overnight. Cells were incubatedwith the compound for 30 min and 24 hours and whole cell lysate washarvested by adding 1×SDS Sample Buffer (62.5 mM Tris-HCl (pH 6.8 at 25°C.), 2% w/v SDS, 10% glycerol, 50 mM DTI, and 0.01% w/v bromophenol blueor phenol red). Proteins were separated by SDS-PAGE electrophoresis andtransferred to PVDF membrane. Protein expression was immunobloted byvarious primary antibodies and detected by Immobilon WesternChemiluminescent HRP Substrate (Millipore). Antibody against Akt,phosphor-Akt (Ser473), phosphor-Akt (Thr308), p70 S6 Kinase,phosphor-p70 S6 Kinase (Thr389), 4E-BP1, and phosphor-4E-BP1 (Thr37/46)were purchased form Cell Signaling Technology.

(3) mTOR Kinase Assay

The activity of the compound against mTOR was examined by measuring theincorporation of ³³P from [γ-³³P]-ATP into 4EBP1. His-tagged,recombinant human 4EBP1 was expressed in E. coli, purified bynickel-nitrilotriacetic acid (Ni-NTA) resins, and stored at −80° C.Phosphorylation of 4EBP1 by mTOR was assayed in the presence or absenceof the compound and performed in a final volume of 25 μl reaction buffercontaining 300 ng 4EBP1, 50 ng recombinant mTOR (Invitrogen), 50 mMHEPES (pH 7.5), 1 mM EGTA, 0.01% Polysorbate 20, 10 mM MnCl₂, 2.5 mMDTT, 10 μM ATP, and 0.5 μCi [γ-33P]-ATP (PerkinElmer) for 30 min at 30°C. The reactions were terminated by adding 3% phosphoric acid. The ³³Plabeled 4EBP1 was transferred onto UniFilter-96 GF/B plate (PerkinElmer)and quantified by Top Count Microplate Scintillation Counter(PerkinElmer). For primary screening of kinase activity inhibition, eachtest compound was evaluated at 10 M in duplicate. The results were theaverage of duplicate measurements and expressed as percentage inhibition(compound treatment versus DMSO control). The IC₅₀ values of thecompounds were determined after carrying out assays at eight seriallydiluted concentrations of each compound in duplicate. The results wereanalyzed using linear regression software (GraphPad Prism 5; GraphPadSoftware Inc.).

(4) PI3K Enzyme Assay

The ability of compounds at 500 nM against phosphatidylinositide3-kinase (PI3K) was verified by PI3K HTRF Assay. Recombinant PI3K(p110α/p85α) and PI3K (p110β/p85α) were from Millipore. Enzyme reactionswere performed according to the manufacturer's suggestions. Briefly, thecompounds of interest dissolved in 100% DMSO were dispensed in allwells, following which the mixture of PIP2 and enzyme was added. PI3K(p110α/p85α) and PI3K (p110β/p85α) enzyme reactions were initiated inthe presence of 10 μM and 100 μM ATP, respectively, and incubated for 30min at room temperature. STOP solution prepared 2 hours prior to use wasadded to stop reactions, and mixed well. Detection solution prepared 2hours prior to use was added, and incubated at room temperature for 17hours in the dark. Fluorescence was measures by Packard Fusion AlphaMicroplate Analyzer with excitation at 340 nm and emission at 620 nm and665 nm. HTRF ration was calculated as follows:

${{HTRF}\mspace{14mu} {ratio}} = {\frac{{emission}\mspace{14mu} {at}\mspace{14mu} 665\mspace{14mu} {nm}}{{emission}\mspace{14mu} {at}\mspace{14mu} 620\mspace{14mu} {nm}} \times 10000}$

Biological Activity

Inhibition of mTOR kinase by various compounds listed above aresummarized and shown in Table 1 and Table 2 below. IC₅₀ value is definedas the concentration of the test compound which achieves a half-maximalinhibition of the kinase activity.

Inhibition of PI3K alpha and PI3K beta by mTOR compounds at 500 nM aresummarized and shown in Table 3.

Effects on cellular proliferation by the various compounds of thepresent invention are summarized and shown in Table 4 below.

Inhibition effects of compounds of interest on PI3K/Akt/mTOR signaltransduction pathway in PC-3 cell are summarized and shown in Table 5below.

TABLE 1 % Inhibition Compound @ 10 μM MTR-0037 98% MTR-0043 96% MTR-005481% MTR-0069 98% MTR-0073 86% MTR-0077 87% MTR-0079 83% MTR-0081 95%MTR-0083 99% MTR-0091 92% MTR-0098 86% MTR-0102 81% MTR-0106 96%MTR-0108 89% MTR-0116 81% MTR-0118 94% MTR-0120 98% MTR-0121 94%MTR-0123 91% MTR-0124 99% MTR-0125 96% MTR-0128 99% MTR-0129 96%MTR-0132 98% MTR-0133 93% MTR-0135 90% MTR-0137 84% MTR-0139 85%MTR-0141 96% MTR-0142 98% MTR-0145 100%  MTR-0147 95% MTR-0149 93%MTR-0150 87% MTR-0152 98% MTR-0159 97% MTR-162 95% MTR-0164 91% MTR-016599% MTR-0167 89% MTR-0168 91% MTR-0169 96% MTR-0172 86% MTR-173 92%MTR-0176 96% MTR-0177 84% MTR-0178 90% MTR-0182 99% MTR-0183 95%MTR-0184 98% MTR-0185 99% MTR-0186 96% MTR-0191 100%  MTR-0193 81%MTR-0195 101%  MTR-0197 97% MTR-0198 87% MTR-0199 99% MTR-0200 84%MTR-0202 96% MTR-0205 100%  MTR-0210 96% MTR-0211 98% MTR-0212 85%MTR-0213 84% MTR-0215 96% MTR-0216 94% MTR-0220 102%  MTR-0221 101% MTR-0222 93% MTR-0225 101%  MTR-0226 90% MTR-0227 99% MTR-0228 101% MTR-0229 100%  MTR-0231 97% MTR-0232 95% MTR-0233 91% MTR-0236 98%MTR-0237 85% MTR-0238 95% MTR-0239 89% MTR-0241 99% MTR-0242 96%MTR-0243 92% MTR-0244 99% MTR-0245 94% MTR-0246 96% MTR-0248 95%MTR-0249 97% MTR-0250 98% MTR-0251 98% MTR-0252 82% MTR-0253 99%MTR-0256 90% MTR-0257 93% MTR-0261 98% MTR-0262 90% MTR-0264 86%MTR-0265 96% MTR-0266 96% MTR-0267 98% MTR-0268 97% MTR-0270 96%MTR-0271 98% MTR-0273 99% MTR-0274 99% MTR-0275 97% MTR-0276 82%MTR-0277 99% MTR-0278 100%  MTR-0280 95% MTR-0282 99% MTR-0283 100% MTR-0286 93% MTR-0288 98% MTR-0289 91% MTR-0291 89% MTR-0293 83%MTR-0297 83% MTR-0299 97% MTR-0303 90% MTR-0304 90% MTR-0305 82%MTR-0306 90% MTR-0307 82% MTR-0308 93% MTR-0310 86% MTR-0312 94%MTR-0313 98% MTR-0314 98% MTR-0316 99% MTR-0317 93% MTR-0318 91%MTR-0319 84% MTR-0322 94% MTR-0323 100%  MTR-0324 81% MTR-0325 100% MTR-0326 101%  MTR-0328 85% MTR-0329 97% MTR-0334 93% MTR-0335 89%MTR-0336 89% MTR-0337 96% MTR-0338 94% MTR-0341 83% MTR-0343 92%MTR-0344 92% MTR-0345 95% MTR-0347 96% MTR-0350 95% MTR-0351 99%MTR-0352 94% MTR-0353 96% MTR-0356 82% MTR-0358 100%  MTR-0360 95%MTR-0361 95% MTR-0362 84% MTR-0363 93% MTR-0364 100%  MTR-0365 99%MTR-0366 85% MTR-0368 97% MTR-0369 98% MTR-0370 97% MTR-0372 96%MTR-0373 81% MTR-0376 96% MTR-0377 97% MTR-0378 96% MTR-0380 91%MTR-0381 92% MTR-0382 99% MTR-0385 98% MTR-0387 96% MTR-0388 100% MTR-0391 100%  MTR-0392 102%  MTR-0394 101%  MTR-0398 89% MTR-0400 85%MTR-0401 101%  MTR-0403 88% MTR-0404 97% MTR-0405 97% MTR-0406 97%MTR-0407 96% MTR-0410 85% MTR-0411 93% MTR-0412 98% MTR-0415 81%MTR-0419 82% MTR-0420 92% MTR-0421 99% MTR-0423 95% MTR-0424 100% MTR-0426 97% MTR-0427 97% MTR-0430 86% MTR-0435 90% MTR-0436 99%MTR-0438 99% MTR-0440 89% MTR-0442 96% MTR-0443 100%  MTR-0446 101% MTR-0449 100%  MTR-0452 100%  MTR-0453 101%  MTR-0454 100%  MTR-0455100%  MTR-0456 101%  MTR-0457 98% MTR-0459 88% MTR-0461 99% MTR-0462 99%MTR-0463 97% MTR-0464 96% MTR-0465 97% MTR-0468 97% MTR-0469 93%MTR-0470 88% MTR-0471 94% MTR-0472 95% MTR-0474 88% MTR-0476 99%MTR-0477 99% MTR-0478 99% MTR-0479 95% MTR-0480 90% MTR-0481 98%MTR-0483 88% MTR-0484 95% MTR-0485 100%  MTR-0486 88% MTR-0487 98%MTR-0488 94% MTR-0489 96% MTR-0490 102%  MTR-0491 100%  MTR-0492 100% MTR-0493 99% MTR-0494 86% MTR-0495 100%  MTr-0496 95%

TABLE 2 IC₅₀ of Compounds Kinase [nM] MTR-0069 142.6 MTR-0081 292.3MTR-0083 107.2 MTR-0106 234.9 MTR-0124 102.5 MTR-0128 253.4 MTR-0132116.3 MTR-0142 257.3 MTR-0152 206.8 MTR-0165 233.2 MTR-0173 198.1MTR-0176 210.1 MTR-0182 275.3 MTR-0184 102.3 MTR-0185 223.5 MTR-0195116.4 MTR-0197 110.4 MTR-0199 161.8 MTR-0202 253.6 MTR-0205 116.4MTR-0211 226.9 MTR-0215 52.5 MTR-0216 133.9 MTR-0220 72.2 MTR-0221 134.6MTR-0222 11.5 MTR-0225 101.2 MTR-0226 212.6 MTR-0227 18.8 MTR-0228 82.6MTR-0229 241 MTR-0231 105.2 MTR-0232 184.7 MTR-0233 80.1 MTR-0236 80.7MTR-0238 225.2 MTR-0241 8.1 MTR-0242 107.2 MTR-0244 18 MTR-0246 228.1MTR-0248 96.4 MTR-0249 116.7 MTR-0250 150.2 MTR-0251 146.1 MTR-0253 62.5MTR-0257 74.4 MTR-0261 86.8 MTR-0262 8 MTR-0265 171.9 MTR-0266 256.7MTR-0267 109.1 MTR-0268 237.7 MTR-0271 89.6 MTR-0273 81.1 MTR-0274 105.6MTR-0277 78.3 MTR-0278 67 MTR-0282 47.7 MTR-0283 30.5 MTR-0288 78.9MTR-0299 177 MTR-0303 237.9 MTR-0308 48.6 MTR-0313 214.3 MTR-0314 169.7MTR-0316 93.9 MTR-0322 93 MTR-0323 50.1 MTR-0325 24.8 MTR-0326 40.9MTR-0337 272.2 MTR-0347 174.5 MTR-0351 65.7 MTR-0353 194.6 MTR-0358 26.8MTR-0364 70.4 MTR-0365 179.9 MTR-0368 83.4 MTR-0369 214.1 MTR-0370 86MTR-0372 202.4 MTR-0376 130.3 MTR-0378 133.2 MTR-0380 221.2 MTR-038267.7 MTR-0385 215 MTR-0387 140.8 MTR-0388 79.6 MTR-0391 5.4 MTR-039219.6 MTR-0394 70.4 MTR-0401 64.8 MTR-0404 148.5 MTR-0405 49.5 MTR-0406179.7 MTR-0407 219.5 MTR-0412 136.93 MTR-0420 65.7 MTR-0421 58.8MTR-0424 30.1 MTR-0426 173.9 MTR-0427 97.7 MTR-0436 69.4 MTR-0438 51.1MTR-0442 39 MTR-0443 76.8 MTR-0446 56.6 MTR-0449 79.2 MTR-0452 155.1MTR-0453 30.2 MTR-0454 110.9 MTR-0455 42.3 MTR-0456 119.3 MTR-0457 5.8MTR-0461 138.2 MTR-0462 101.1 MTR-0463 47.8 MTR-0464 75.1 MTR-0465 124.1MTR-0469 193.5 MTR-0471 252 MTR-0472 117.4 MTR-0476 175.9 MTR-0477 23.7MTR-0478 25.1 MTR-0481 169.3 MTR-0484 58.1 MTR-0487 86.7 MTR-0488 255.5MTR-0489 267.7

TABLE 3 % inhibition @ 500 nM Compound p110α p110β MTR-0043 85.40%44.80% MTR-0069 53.80% 4.10% MTR-0083 44.80% 9.00% MTR-0091 60.90%16.20% MTR-0124 49.10% −2.60% MTR-0128 85.80% 17.30% MTR-0133 70.00%4.50% MTR-0135 70.10% 14.20% MTR-0147 52.40% 1.20% MTR-0152 83.00%35.70% MTR-0162 102.20% 33.90% MTR-0164 84.70% 42.10% MTR-0165 100.80%66.20% MTR-0168 65.00% 20.20% MTR-0169 52.70% 3.20% MTR-0173 82.10%32.40% MTR-0178 48.80% 8.20% MTR-0197 59.80% 20.30% MTR-0205 42.60%6.00% MTR-0211 42.00% 24.40% MTR-0215 53.60% 24.10% MTR-0222 44.30%16.50% MTR-0225 43.80% 14.30% MTR-0226 45.70% 25.20% MTR-0227 87.00%38.20% MTR-0228 74.40% 33.20% MTR-0236 61.20% 17.60% MTR-0241 94.80%53.70% MTR-0242 96.30% 22.80% MTR-0244 60.00% 26.30% MTR-0246 43.30%10.90% MTR-0248 45.80% 3.60% MTR-0257 95.50% 62.40% MTR-0261 58.40%8.80% MTR-0262 56.30% 18.00% MTR-0267 83.70% 54.10% MTR-0270 41.10%20.00% MTR-0271 94.50% 53.80% MTR-0273 50.20% 28.30% MTR-0274 59.00%28.40% MTR-0277 61.90% 56.50% MTR-0278 58.60% 31.00% MTR-0282 76.80%53.90% MTR-0283 72.90% 53.40% MTR-0288 79.20% 32.60% MTR-0299 44.30%6.70% MTR-0308 106.50% 37.50% MTR-0313 86.90% 30.40% MTR-0316 55.90%27.90% MTR-0322 44.20% 13.20% MTR-0323 90.80% 49.50% MTR-0325 91.50%36.90% MTR-0326 90.70% 42.30% MTR-0347 80.60% 63.50% MTR-0351 52.30%32.00% MTR-0358 97.80% 97.80% MTR-0368 101.40% 60.90% MTR-0370 61.80%40.80% MTR-0372 95.50% 47.90% MTR-0376 79.40% 47.90% MTR-0378 84.50%30.00% MTR-0380 100.60% 67.00% MTR-0382 95.90% 53.30% MTR-0385 64.00%36.80% MTR-0387 83.10% 27.70% MTR-0391 51.70% 29.10% MTR-0392 46.60%31.30% MTR-0394 70.50% 67.20% MTR-0398 47.00% 21.80% MTR-0401 41.70%16.20% MTR-0404 66.90% 22.70% MTR-0405 52.50% 23.60% MTR-0406 78.40%56.90% MTR-0407 63.40% 48.60% MTR-0412 82.70% 53.00% MTR-0420 58.60%8.30% MTR-0421 98.70% 51.30% MTR-0424 71.50% 27.10% MTR-0426 58.40%39.70% MTR-0427 71.10% 76.20% MTR-0436 71.50% 51.90% MTR-0442 79.10%48.50% MTR-0446 66.30% 40.70% MTR-0449 75.40% 92.50% MTR-0454 74.40%30.30% MTR-0455 48.90% 19.80% MTR-0456 52.60% 30.60% MTR-0457 47.40%22.30% MTR-0461 93.40% 46.70% MTR-0462 67.90% 38.30% MTR-0469 81.70%70.70%

TABLE 4 IC₅₀, nM Compound A549 PC3 MTR-0124 566 ± 12 390 ± 9  MTR-0128914 ± 29 499 ± 45 MTR-0142 488 ± 56 416 ± 90 MTR-0145 1358 ± 340 432 ±20 MTR-0191 373 ± 14 374 ± 18 MTR-0197 115 ± 2  18 ± 1 MTR-0205 673 ± 19130 ± 5  MTR-0221 710 ± 76 327 ± 43 MTR-0222  88 ± 17 30 ± 7 MTR-02251535 ± 113 333 ± 24 MTR-0227 223 ± 20 49 ± 3 MTR-0228 1029 ± 114 193 ±8  MTR-0241 129 ± 5  61 ± 4 MTR-0242  748 ± 140 286 ± 1  MTR-0244 891 ±64 70 ± 9 MTR-0246 1449 ± 29  433 ± 10 MTR-0248 145 ± 5  178 ± 27MTR-0250 834 ± 37 305 ± 24 MTR-0251 2062 ± 75  456 ± 23 MTR-0253 2478 ±367 268 ± 44 MTR-0257 501 ± 23 119 ± 14 MTR-0261 512 ± 25 111 ± 2 MTR-0262 561 ± 49 130 ± 4  MTR-0267 3492 ± 156 207 ± 7  MTR-0271 155 ±1  97 ± 4 MTR-0273 660 ± 40 162 ± 6  MTR-0274 135 ± 11 57 ± 2 MTR-0277561 ± 30 86 ± 3 MTR-0278 67 ± 3 39 ± 0 MTR-0280 382 ± 23 126 ± 8 MTR-0282 7571 ± 755 148 ± 14 MTR-0283 3721 ± 341 283 ± 31 MTR-0288 3982± 275 252 ± 27 MTR-0299 2499 ± 49  384 ± 39 MTR-0303 223 ± 8  46 ± 1MTR-0308 219 ± 11 62 ± 2 MTR-0322 302 ± 1  109 ± 0  MTR-0323 1041 ± 23 86 ± 3 MTR-0325 53 ± 2 16 ± 1 MTR-0326 1029 ± 19  147 ± 10 MTR-0337 457± 38 154 ± 6  MTR-0347 313 ± 3  154 ± 8  MTR-0350 614 ± 28 188 ± 6 MTR-0353 557 ± 7  396 ± 6  MTR-0358 144 ± 1  34 ± 1 MTR-0364 462 ± 8 142 ± 14 MTR-0365 74 ± 5 23 ± 1 MTR-0368 214 ± 2  74 ± 2 MTR-0369 280 ±6  44 ± 4 MTR-0370 287 ± 5  92 ± 4 MTR-0372 332 ± 20 204 ± 7  MTR-0376595 ± 33 142 ± 10 MTR-0377 598 ± 18 205 ± 6  MTR-0378 186 ± 3  113 ± 11MTR-0382 74 ± 5 19 ± 1 MTR-0385 361 ± 13 396 ± 6  MTR-0387 148 ± 10 88 ±3 MTR-0388 250 ± 8  136 ± 3  MTR-0391  6 ± 0  8 ± 0 MTR-0392 188 ± 7  22± 0 MTR-0394 431 ± 10 71 ± 2 MTR-0398 460 ± 28 179 ± 14 MTR-0401 685 ±35 169 ± 3  MTR-0404 273 ± 1  109 ± 0  MTR-0405 88 ± 6 74 ± 2MTR-0406 >10000 285 ± 5  MTR-0407 >10000 386 ± 16 MTR-0420 234 ± 1  148± 2  MTR-0421 87 ± 1 37 ± 1 MTR-0424 118 ± 2  51 ± 1 MTR-0426 962 ± 58282 ± 11 MTR-0427 1798 ± 52  125 ± 2  MTR-0436 299 ± 10 78 ± 4 MTR-0438116 ± 4  48 ± 1 MTR-0442 392 ± 15 110 ± 10 MTR-0443 529 ± 7  131 ± 6 MTR-0446 379 ± 13 130 ± 8  MTR-0449 1050 ± 12  95 ± 7 MTR-0452 82 ± 3 32± 1 MTR-0453 206 ± 1  56 ± 2 MTR-0454 215 ± 1  54 ± 1 MTR-0455 309 ± 1672 ± 2 MTR-0456 2088 ± 34  362 ± 25 MTR-0457  11 ± 0.2  6.5 ± 0.3MTR-0461 177 ± 3  64 ± 2 MTR-0462 448 ± 23 182 ± 6  MTR-0463 222 ± 15 32± 1 MTR-0464  12 ± 0.8 2.4 ± 0  MTR-0465 197 ± 3  137 ± 2  MTR-0469 39 ±2 5.7 ± 0  MTR-0471 34 ± 2 MTR-0472 226 ± 19 MTR-0476 137 ± 6  15 ± 0MTR-0477 122 ± 1  102 ± 1  MTR-0478 107 ± 4  102 ± 1  MTR-0481 608 ± 14424 ± 26

TABLE 5 IC₅₀ (nM) p-S6K p-Akt S473 p-Akt T308 compound (mTORC1) (mTORC2)(PI3K) PI-103 64.86 35.61 86.73 GDC-0941 451.34 11.49 158.49 BEZ-235 <1028.91 892.1 Rapamycin <10 <10 >1000 MTR-0227 11.64 184.73 141.29MTR-0325 <10 74.49 >1000 MTR-0358 <10 491.45 >1000 MTR-0391 <10 19.14290.64 MTR-0392 35.03 17.91 <10 MTR-0394 <10 11.11 <10

What is claimed is:
 1. A method of treating mTOR kinase-/PI3Kkinase-related diseases in a subject in need thereof which comprisesadministering to the subject an effective amount of a compound offormula (I):

wherein R¹ is selected from: (i) a group of the following formula:

wherein P is aryl or heteroaryl which is unsubstituted or substituted,when P is a benzoimidazole group, said benzoimidazole group is attachedto the pyrimidinyl group in formula (I) through its benzene ring; Q isselected from —H, —OR, —SR, -Halo, —NR₃R₄, —OS(O)_(m)R, —OC(O)R,—OC(O)NHR, —S(O)_(m)NR₃R₄, —NRC(O)R, —NRS(O)_(m)R, —NRC(O)NR₃R₄, and—NRC(S)NR₃R₄, wherein each R, R₃, and R₄ is independently selected fromH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl and a 5- to 12-membered carbocyclicgroup, aryl or heteroaryl group, the group being unsubstituted orsubstituted; m is 1 or 2; or R₃ and R₄, which are the same or different,are each independently selected from H, C₁-C₆ alkyl which isunsubstituted or substituted, C₃-C₁₀ cycloalkyl which is unsubstitutedor substituted, —C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are asdefined above, or R₃ and R₄ together with the nitrogen atom to whichthey are attached form a saturated 5-, 6- or 7-membered N-containingheterocyclic group which is unsubstituted or substituted; —C(O)R,—C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above; Y isselected from —O—(CH₂)_(n)—, —S—(CH₂)_(n)—, and —S(O)_(m)(CH₂)_(n)—wherein m is 1 or 2, n is 0 or an integer of 1 to 3, and R² is selectedfrom H or a 5- to 12-membered carbocyclic or heterocyclic group which isunsubstituted or substituted, and a group —NR₃R₄ wherein R₃ and R₄ areas defined above; Z is selected from (i) halo, —(CH₂)_(s)COOR,—(CH₂)_(s)CHO, —(CH₂)CH₂OR, —(CH₂)_(s)CONR₃R₄, —(CH₂)_(s)CH₂NR₃R₄,—NR₃R₄ and —O(CH₂)_(s)NR₃R₄ wherein s is 0 or an integer of 1 to 2 andwherein R, R₃ and R₄ are as defined above; (ii) substituted orunsubstituted heteroaryl, (iii) substituted or unsubstitutedheterocyclyl, (iv) substituted or unsubstituted aryl, and (v)substituted or unsubstituted C₁-C₆-alkyl; and W is selected from (i)NR₅R₆, wherein R₅ and R₆ form, together with the N atom to which theyare attached, a morpholine ring which is unsubstituted or substituted,(ii) substituted or unsubstituted heteroaryl, (iii) substituted orunsubstituted heterocyclyl, (iv) substituted or unsubstituted aryl, and(v) substituted or unsubstituted C₁-C₆-alkyl; or a stereoisomer, or atautomer, or an N-oxide, or a pharmaceutically acceptable salt, or anester, or a prodrug, or a hydrate, or a solvate thereof.
 2. A methodaccording to claim 1, wherein the mTOR kinase-/PI3K kinase-relateddisease is selected from cancer, immune disorders, cardiovasculardisease, viral infection, inflammation, metabolism/endocrine functiondisorders and neurological disorders.
 3. A method according to claim 2,wherein the cancer is a Epidermal Growth Factor Receptor (EGFR)dependent cancer or a cancer that resists to EGFR targeting agent.
 4. Amethod according to claim 2, which comprises administering to thesubject a further therapeutic agent.
 5. A method according to claim 4,wherein the further therapeutic agent is a protein kinase inhibitor, anantibody, an alkylating agent, a mitotic inhibitor, an antimetabolite, acell cycle inhibitor, an enzyme, a hormone, an anti-hormone, agrowth-factor inhibitor, a plant alkaloid and terpenoid, a topoisomeraseinhibitor, an antitumor antibiotic, a vinca alkaloid, a taxane, aplatinum agent, a thalidomide or relative analog, an antiangiogenicagent, or a combination thereof.
 6. A method of treating mTORkinase-/PI3K kinase-related diseases in a subject in need thereof whichcomprises administering to the subject an effective amount of a compoundselected from:5-Ethoxy-2-(3-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0037)5-Ethoxy-2-(4-hydroxy-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0038)5-Ethoxy-2-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0039)2-(3-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0040)3-[4-(2-Dimethylamino-ethoxy)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenol(MTR-0043)3-[4-(2-Dimethylamino-ethoxy)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenol(MTR-0046) 3-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0047)2-(3,5-Difluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0053)5-Ethoxy-2-(1H-indol-5-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic acidethyl ester (MTR-0054)5-Ethoxy-2-(1H-indol-6-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylic acidethyl ester (MTR-0055)2-Benzo[1,3]dioxol-5-yl-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0056)5-Ethoxy-2-(1H-indazol-4-yl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0057)5-Ethoxy-2-(2-fluoro-3-methoxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0058)2-{3-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0059)5-Ethoxy-6-morpholin-4-yl-2-[3-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0060)2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0068)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0069)2-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0070)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0071)2-(3-Hydroxy-phenyl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0073)5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indole(MTR-0074)2-(1H-Indazol-4-yl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0075)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-Chloro-3-trifluoromethyl-phenyl)-urea(MTR-0076)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-Chloro-pyridin-3-yl)-urea(MTR-0077)N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-acetamide(MTR-0078)2-{4-[3-(6-Chloro-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0079)5-Ethoxy-2-[4-(3-ethyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0081)[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0083)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-1H-indazole(MTR-0084) Methanesulfonic acid3-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester (MTR-0086)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0091)3-(4-Chloro-5-methanesulfonyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol(MTR-0094)N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide(MTR-0096)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol(MTR-0098) Methanesulfonic acid4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester (MTR-0100)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-thioureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0102)2-(4-Benzenesulfonylamino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0103)1-(2-Chloro-ethyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0108)5-Ethoxy-2-(4-hydroxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0111)5-Ethoxy-2-(4-ethylcarbamoyloxy-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0112)5-Ethoxy-6-morpholin-4-yl-2-(4-phenylcarbamoyloxy-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (MTR-0113) (2-Chloro-ethyl)-carbamic acid4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester (MTR-0114) Benzenesulfonic acid4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylester (MTR-0115) 3-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenol(MTR-0116)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (MTR-0118)N-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-benzenesulfonamide(MTR-0119)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid diethylamide (MTR-0120)5-Ethoxy-6-morpholin-4-yl-2-(4-ureido-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (MTR-0121)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-dimethylamino-phenyl)-urea(MTR-0123)1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0124)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid amide (MTR-0125) Phenyl-carbamic acid4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl ester (MTR-0127)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0128)1-Ethyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0129) Ethyl-carbamic acid4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl ester (MTR-0130)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-benzenesulfonamide(MTR-0131)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-ethyl-urea(MTR-0132)5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-ylamine(MTR-0133)1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-phenyl-urea(MTR-0134)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-fluoro-phenyl)-urea(MTR-0135)1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-ethyl-urea(MTR-0136)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-phenyl)-urea(MTR-0137)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-difluoro-phenyl)-urea(MTR-0138)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (2-morpholin-4-yl-ethyl)-amide (MTR-0139)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (MTR-0140)1-{4-[5-Ethoxy-4-morpholin-4-yl-6-(pyrrolidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0141)1-{4-[5-Ethoxy-4-morpholin-4-yl-6-(piperidine-1-carbonyl)-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0142)1-[5-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea(MTR-0143)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (2-diethylamino-ethyl)-amide (MTR-0144)1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0145)2-(6-Amino-pyridin-3-yl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0146)5-Ethoxy-2-{4-[3-(3-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0147)5-Ethoxy-6-morpholin-4-yl-2-[6-(3-phenyl-ureido)-pyridin-3-yl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0148)5-Ethoxy-2-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0149)2-{4-[3-(3,4-Difluoro-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0150)1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea (MTR-0152)4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (MTR-0153)4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0154) 4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenol(MTR-0155)5-Ethoxy-2-{6-[3-(4-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0156)2-{6-[3-(3,4-Difluoro-phenyl)-ureido]-pyridin-3-yl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0157)5-Ethoxy-2-{6-[3-(3-fluoro-phenyl)-ureido]-pyridin-3-yl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0158)1-Ethyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0159)4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole(MTR-0160)4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine(MTR-0161)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0162)4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-benzenesulfonamide(MTR-0163)1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0164)1-(3,4-Difluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0165)[2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidin-4-yl]-methanol(MTR-0166)1-(4-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea (MTR-0167)1-(3-Fluoro-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea (MTR-0168)1-{4-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0169)4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-1H-indazole(MTR-0170)4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenylamine(MTR-0171)1-{4-[5-Ethoxy-4-(4-methyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0172)1-{4-[4-(4-Methanesulfonyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0173)4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-1H-indazole(MTR-0174)4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenylamine(MTR-0175)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-morpholin-4-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0176)1-(3,4-Difluoro-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0177)1-(4-Fluoro-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0178)3-[5-Ethoxy-4-(4-methanesulfonyl-piperazin-1-ylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol(MTR-0180)2-(4-Amino-phenyl)-5-methoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0181)5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0182)5-Methoxy-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (MTR-0183)1-{4-[5-Methoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0184)1-{4-[4-(4-Methanesulfonyl-piperazine-1-carbonyl)-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0185)1-{4-[5-Ethoxy-4-(4-methyl-piperazine-1-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-phenyl-urea(MTR-0186)[2-(4-Amino-phenyl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-aceticacid methyl ester (MTR-0187){5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid methyl ester (MTR-0188){5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-aceticacid (MTR-0189)2-{5-Methylsulfanyl-6-morpholin-4-yl-2-[4-(3-phenyl-ureido)-phenyl]-pyrimidin-4-yl}-acetamide(MTR-0192)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-piperidin-1-ylmethyl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0193)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea(MTR-0195)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-morpholin-4-yl-urea(MTR-0196)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0197)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea(MTR-0198)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(2-dimethylamino-ethoxy)-phenyl]-urea(MTR-0199)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea(MTR-0200)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methyl-piperazin-1-yl)-urea(MTR-0201)5-Ethoxy-2-[4-(3-methyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0202)5-Ethoxy-2-{4-[(morpholine-4-carbonyl)-amino]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0203)2-{4-[3-(3-Dimethylamino-propyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0204)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0205)5-Ethoxy-2-{4-[3-(4-methyl-piperazin-1-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0206)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea(MTR-0207)1-(3-Dimethylamino-propyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0208)1-(4-Methyl-piperazin-1-yl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0209)1-Methyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0210)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-fluoro-4-morpholin-4-yl-phenyl)-urea(MTR-0211)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid ethyl ester (MTR-0212)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0213)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(MTR-0214)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea(MTR-0215)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea(MTR-0216)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-morpholin-4-yl-ethyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0217)5-Ethoxy-6-morpholin-4-yl-2-(2-phenylamino-1H-benzoimidazol-5-yl)-pyrimidine-4-carboxylicacid ethyl ester (MTR-0218)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-morpholin-4-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0219)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-thiazol-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0220)5-Ethoxy-2-{4-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0221)5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (MTR-0222)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0223)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-morpholin-4-yl-urea(MTR-0224)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0225)1-(3-Fluoro-4-morpholin-4-yl-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0226)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0227)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0228)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-methyl-urea(MTR-0229)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-2-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid ethyl ester (MTR-0230)5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0231)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-thiomorpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0232)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-morpholin-4-yl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0233)2-{4-[3-(2-Amino-phenyl)-thioureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0234)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea(MTR-0235)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea(MTR-0236)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea(MTR-0237)1-{4-[4-(4-Methyl-piperazin-1-yl)-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea(MTR-0238)1-(3,4-Dimethoxy-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0239)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(MTR-0240)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0241)1-(3-Fluoro-4-morpholin-4-yl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0242)2-[4-(1H-Benzoimidazol-2-ylamino)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0243)2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0244)5-Ethoxy-6-morpholin-4-yl-2-[4-(3-pyridin-3-yl-ureido)-phenyl]-pyrimidine-4-carboxylicacid (MTR-0245)1-[4-(4-Methyl-piperazin-1-yl)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0246)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea(MTR-0247)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea(MTR-0248)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea(MTR-0249)2-{4-[3-(3-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0250)2-{4-[3-(3-Carbamoyl-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0251)5-Ethoxy-6-morpholin-4-yl-2-(4-{3-[3-(2,2,2-trifluoro-acetylamino)-phenyl]-ureido}-phenyl)-pyrimidine-4-carboxylicacid ethyl ester (MTR-0252)1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-pyridin-3-yl-urea(MTR-0253)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea(MTR-0254)2-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-thiophene-3-carboxylicacid methyl ester (MTR-0255)1-Benzo[1,3]dioxol-5-yl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0256)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0257)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3,4-dimethoxy-phenyl)-urea(MTR-0258)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-morpholin-4-yl-ethyl)-urea(MTR-259)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-penta-2,4-dienyl]-3-(4-methyl-piperazin-1-yl)-urea(MTR-0260)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-morpholin-4-yl-phenyl)-urea(MTR-0261)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea(MTR-0262)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea(MTR-0263)4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid ethyl ester (MTR-0264)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea(MTR-0265)1-[6-(4-Methyl-piperazin-1-yl)-pyridin-3-yl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0266)4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0267)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-urea(MTR-0268)N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide(MTR-0269)N-(3-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0270)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-urea(MTR-0271)[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester (MTR-0272)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(4-sulfamoyl-phenyl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0273)5-Ethoxy-2-(4-{3-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0274)5-Ethoxy-2-(4-{3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0275)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(6-morpholin-4-yl-pyridin-3-yl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0276)2-(4-{3-[4-(2-Dimethylamino-ethylcarbamoyl)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0277)5-Ethoxy-2-(4-{3-[4-(morpholine-4-carbonyl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0278){4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-carbamicacid phenyl ester (MTR-0279)1-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0280)[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acidphenyl ester (MTR-0281)4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0282)4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide(MTR-0283)4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-2-nitro-phenylamine(MTR-0284)1-(2-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea(MTR-0285)[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0286)1-(2-Amino-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea(MTR-0287)4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide(MTR-0288)(1H-Benzoimidazol-2-yl)-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine(MTR-0289)[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester (MTR-0290)1-(6-Bromo-pyridin-3-yl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0291)1-(2-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thiourea(MTR-0292)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-thioureido}-benzoicacid (MTR-0293)5-Ethoxy-2-(4-{3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0294)5-Ethoxy-2-{4-[3-(2-methoxycarbonyl-thiophen-3-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0296)5-Ethoxy-2-{4-[3-(1H-indazol-4-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0297)5-Ethoxy-2-{4-[3-(4-methyl-1H-benzotriazol-5-yl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0298)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-ureido]-phenyl}I-pyrimidine-4-carboxylicacid ethyl ester (MTR-0299)2-(4-Amino-3-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0300)5-Ethoxy-2-(3-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0301)5-Ethoxy-2-(3-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0302)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea(MTR-0303)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea(MTR-0304)(1H-Benzoimidazol-2-yl)-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine(MTR-0305)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isopropyl-urea(MTR-0306)[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-carbamic acid (MTR-0307)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea(MTR-0308)4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-benzene-1,2-diamine(MTR-0309)(1H-Benzoimidazol-2-yl)-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amine(MTR-0310)5-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1H-benzoimidazol-2-ylamine(MTR-0311)1-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0312)3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0313)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-thiazol-2-yl-urea(MTR-0314)1-(3,4-Dimethoxy-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0315)4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid (MTR-0316)1-Benzo[1,3]dioxol-5-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0317)1-[5-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0318)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea(MTR-0319)2-(4-Amino-2-fluoro-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0320)5-Ethoxy-2-(2-fluoro-4-phenoxycarbonylamino-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0321)5-Ethoxy-2-(2-fluoro-4-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0322)4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0323)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-thiomorpholin-4-yl-phenyl)-urea(MTR-0324)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0325)4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide(MTR-0326)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-2-fluoro-phenylamino-urea(MTR-0327)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(5-morpholin-4-yl-pyridin-2-yl)-urea(MTR-0328)1-(4-Amino-phenyl)-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0329)1-tert-Butyl-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0330)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-amino-urea(MTR-0331)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenylamine(MTR-0332)1-tert-Butylamino-3-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0333)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-yl]-urea(MTR-0334)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-thiourea(MTR-0335) [4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0336)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methyl-piperazin-1-yl)-phenyl]-urea(MTR-0337)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-urea(MTR-0338)1-Isopropyl-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0339)1-(6-Bromo-pyridin-3-yl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0340)1-Isopropyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0341)1-tert-Butyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0342)1-[4-(2-Dimethylamino-ethoxy)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0343)2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-3-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0344)2-{4-[3-(4-Carbamoyl-phenyl)-ureido]-2-fluoro-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0345)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(1H-indazol-4-yl)-urea(MTR-0346)N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide(MTR-0347)1,3-Bis-[4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea (MTR-0349)1-(4-Amino-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea (MTR-0350)4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzoicacid (MTR-0351)1-(6-Bromo-pyridin-3-yl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0352)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(6-morpholin-4-yl-pyridin-3-yl)-urea(MTR-0353)[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-carbamicacid phenyl Ester (MTR-0354)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0355)[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-urea(MTR-0356)4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenylamine(MTR-0357)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzenesulfonamide(MTR-0358)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0359)4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0360)2-[4-(3-Benzo[1,3]dioxol-5-yl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0361)5-Ethoxy-2-{4-[3-(4-ethoxycarbonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0362)2-(4-{3-[4-(2-Dimethylamino-ethoxy)-phenyl]-ureido}-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0363)4-(3-{4-[5-Ethoxy-4-(morpholine-4-carbonyl)-6-morpholin-4-yl-pyrimidin-2-yl]-phenyl}-ureido)-benzamide(MTR-0364)5-Ethoxy-2-{4-[3-(4-methanesulfonyl-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0365)5-Ethoxy-2-[4-(3-isopropyl-ureido)-phenyl]-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0366)2-[4-(3-tert-Butyl-ureido)-phenyl]-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0367)N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0368)5-Ethoxy-2-{4-[3-(4-methanesulfonylamino-phenyl)-ureido]-phenyl}-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0369)2-{4-[3-(4-Acetylamino-phenyl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0370)N-(4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0371)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea(MTR-0372)6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine(MTR-0373)1,3-Bis-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0374)3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0375)N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide(MTR-0376)N-(3-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0377)1-[3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0378)N-(4-{3-[3-Fluoro-4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0379)N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0380)1-[4-(5-Methanesulfonyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0381)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea(MTR-0382)2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0383)3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0384)4-{3-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0385)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-2-yl-urea(MTR-0386)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-urea(MTR-0387)[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0388)1-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0389)[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester (MTR-0390)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0391)4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0392)N-(4-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide(MTR-0394)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-urea(MTR-0395) 4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0396) [4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-carbamicacid phenyl ester (MTR-0397)1-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0398)1-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0399)4-{3-[4-(5-Ethoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0400)1-[4-(5-Methanesulfinyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0401)2′-Amino-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylic acidethyl ester (MTR-0402)5-Ethoxy-6-morpholin-4-yl-2′-{3-[4-(3-oxo-morpholin-4-yl)-phenyl]-ureido}-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester (MTR-0403)1-(4-Methanesulfonyl-phenyl)-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0404)1-[2-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0405)1-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0406)4-{3-[3-Fluoro-4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0407)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-thiourea(MTR-0408)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzamide(MTR-0409)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-2-fluoro-phenyl]-ureido}-benzenesulfonamide(MTR-0410)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzamide(MTR-0411)4-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-3-fluoro-phenyl]-ureido}-benzenesulfonamide(MTR-0412)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea(MTR-0413)N-(5-{3-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide(MTR-0415)2′-[3-(4-Carbamoyl-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester (MTR-0417)2′-[3-(4-Acetylamino-phenyl)-ureido]-5-ethoxy-6-morpholin-4-yl-[2,5′]bipyrimidinyl-4-carboxylicacid ethyl ester (MTR-0418)5-Ethoxy-2-(4-{3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-ureido}-phenyl)-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0419)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-urea(MTR-0420)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea(MTR-0421)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea(MTR-0422)5-Ethoxy-6-morpholin-4-yl-2-{4-[3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-ureido]-phenyl}-pyrimidine-4-carboxylicacid ethyl ester (MTR-0423)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(4-methanesulfonyl-phenyl)-urea (MTR-0424)5-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-1,3-dihydro-benzoimidazol-2-one(MTR-0425)N-(3-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-acetamide(MTR-0426)N-(3-Dimethylamino-propyl)-4-{3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-benzamide(MTR-0427) 5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine(MTR-0428)4-[3-(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-ureido]-benzamide(MTR-0429)1-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0430)5-Methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-ylamine(MTR-0431)4-[3-(6-Chloro-5-methylsulfanyl-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-ureido]-benzenesulfonamide(MTR-0432)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea(MTR-0433)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea(MTR-0435)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(4-dimethylamino-piperidine-1-carbonyl)-phenyl]-urea(MTR-0436)4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenylamine(MTR-0437)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea(MTR-0438)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea(MTR-0440)N-(5-{3-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide(MTR-0442)2-{4-[3-(6-Acetylamino-pyridin-3-yl)-ureido]-phenyl}-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylicacid ethyl ester (MTR-0443)N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide(MTR-0444)N-[3-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-2,4-difluoro-benzenesulfonamide(MTR-0445)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0446)1-[4-(5-Ethoxy-4-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0447) 4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0448)N-(4-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide(MTR-0449)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea(MTR-0450)1-(5-Methoxy-4-morpholin-4-yl-[2,5′]bipyrimidinyl-2′-yl)-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0451)1-[4-(5-Ethoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea(MTR-0452)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea (MTR-0453)1-[4-(Morpholine-4-carbonyl)-phenyl]-3-{4-[4-morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-urea(MTR-0454)1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0455)4-(3-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-ureido)-benzamide(MTR-0456)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0457)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-urea(MTR-0459)4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0460)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea(MTR-0461)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0462)N-(4-{3-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-ureido}-phenyl)-methanesulfonamide(MTR-0463)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0464)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-urea (MTR-0465)4-(5-Methylsulfanyl-2,6-di-pyridin-3-yl-pyrimidin-4-yl)-morpholine(MTR-0466)N-[3-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-methanesulfonamide(MTR-0467)1-[4-(5-Methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-phenyl-thiourea(MTR-0468)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0469)1-(4-Methanesulfonyl-phenyl)-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0470)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-sulfonyl)-phenyl]-urea(MTR-0471)1-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0472)1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(morpholine-4-carbonyl)-phenyl]-urea(MTR-0473)1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0474)1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0476)1-Ethyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0477)1-Methyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0478)1-Isopropyl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0479)1-[4-(5-Methoxy-4-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0480)1-{4-[4-Morpholin-4-yl-5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-phenyl}-3-pyridin-4-yl-urea(MTR-0481)4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenylamine(MTR-0482)4-(5-Methoxy-4-morpholin-4-yl-6-(4-aminophenyl-pyrimidin-2-yl)-phenylamine(MTR-0483)1-[4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea(MTR-0484)1-Isoxazol-3-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0485)N-(5-{3-[4-(5-Methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-ureido}-pyridin-2-yl)-acetamide(MTR-0486)1-[4-(4-Methanesulfonyl-piperazin-1-yl)-phenyl]-3-[4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0487)1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0488)1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0489)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0490)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0491)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0492)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0493)1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0494)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0495)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0496)1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0497)1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-4-yl-urea(MTR-0498)1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-pyridin-3-yl-urea(MTR-0499)1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0500)1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0501)1-[4-(5-Methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-urea(MTR-0502)1-[4-(4-Chloro-5-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea(MTR-0503)1-Isoxazol-3-yl-3-[4-(5-methoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0504)1-[4-(4-Chloro-5-ethoxy-6-morpholin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea(MTR-0505)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-4-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea(MTR-0506)1-Isoxazol-3-yl-3-[4-(5-methoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0507)1-[4-(5-Ethoxy-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-3-isoxazol-3-yl-urea(MTR-0508) and1-Isoxazol-3-yl-3-[4-(5-methylsulfanyl-4-morpholin-4-yl-6-pyridin-3-yl-pyrimidin-2-yl)-phenyl]-urea(MTR-0509) or a stereoisomer, or a tautomer, or an N-oxide, or apharmaceutically acceptable salt, or an ester, or a prodrug, or ahydrate, or a solvate thereof.
 7. A method according to claim 6, whereinthe mTOR kinase-/PI3K kinase-related disease is selected from cancer,immune disorders, cardiovascular disease, viral infection, inflammation,metabolism/endocrine function disorders and neurological disorders.
 8. Amethod according to claim 7, wherein the cancer is a Epidermal GrowthFactor Receptor (EGFR) dependent cancer or a cancer that resists to EGFRtargeting agent.
 9. A method according to claim 6, which comprisesadministering to the subject a further therapeutic agent.
 10. A methodaccording to claim 9, wherein the further therapeutic agent is a proteinkinase inhibitor, an antibody, an alkylating agent, a mitotic inhibitor,an antimetabolite, a cell cycle inhibitor, an enzyme, a hormone, ananti-hormone, a growth-factor inhibitor, a plant alkaloid and terpenoid,a topoisomerase inhibitor, an antitumor antibiotic, a vinca alkaloid, ataxane, a platinum agent, a thalidomide or relative analog, anantiangiogenic agent, or a combination thereof.